Piperidinyl-dioxoquinazolines as adenosine reuptake inhibitors

ABSTRACT

The present invention relates to an adenosine uptake inhibitor and an agent for the myocardium protection or the prevention or treatment of inflammatory edema, comprising a 1,2,3,4-tetrahydro-2,4-dioxoquinazoline derivative represented by formula (I): ##STR1## wherein R 1  represents hydrogen, substituted or unsubstituted lower alkyl, alkenyl, or substituted or unsubstituted aralkyl; R 2 , R 3 , R 4 , and R 5  independently represent hydrogen, halogen, amino, mono- or di(lower alkyl)amino, lower alkanoylamino, nitro, cyano, substituted or unsubstituted lower alkyl, hydroxy, lower alkoxy, lower alkylthio, carboxy, lower alkoxycarbonyl, lower alkanoyl, aralkyloxy, or lower alkanoyloxy; R 6 , R 7 , R 8 , and R 9  independently represent hydrogen, hydroxy, substituted or unsubstituted lower alkoxy, or aralkyloxy, or any adjoining two of them are combined to form methylenedioxy; R 10  represents hydrogen or lower alkyl; and Y and Z independently represent N or C--R 11  (wherein R 11  represents hydrogen, substituted or unsubstituted lower alkyl, or halogen), 
     or a pharmaceutically acceptable salt thereof as an active ingredient.

This is a 371 application of PCT/JP94/00229, filed Feb. 16, 1994.

TECHNICAL FIELD

The present invention relates to a drug containing a1,2,3,4-tetrahydro-2,4-dioxoquinazoline derivative or a pharmaceuticallyacceptable salt thereof as an active ingredient, which inhibitsnucleoside uptake of the cells to increase an extracellular adenosineconcentration and is therefore useful for the protection of myocardiumagainst myocardosis due to anoxemia or hypoxia, such as ischemia andreperfusion disorders, and for the prevention or treatment ofinflammation, such as leg and foot edema.

BACKGROUND ART

With respect to 1,2,3,4-tetrahydro-2,4-dioxoquinazoline derivativeshaving a 1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl group at the3-position, those having a hydrogen atom, a chlorine atom or a nitrogroup at the 6-position are described in Chem. Pharm. Bull., 38,1591-1595 (1990). Further, it is known that a compound having adenosineuptake inhibitory activity exhibits myocardium protecting activity[Circul., 80, 1400-1411 (1989); Am. J. Physiol., H1570-1577 (1991); J.Cardiovasc. Pharmacol., 20, 173-178 (1992)].

DISCLOSURE OF THE INVENTION

The present invention relates to an adenosine uptake inhibitor and anagent for the myocardium protection or the prevention or treatment ofinflammatory edema which contain as an active ingredient a1,2,3,4-tetrahydro-2,4-dioxoquinazoline derivative represented byformula (I): ##STR2## wherein R¹ represents hydrogen, substituted orunsubstituted lower alkyl, alkenyl, or substituted or unsubstitutedaralkyl; R², R³, R⁴, and R⁵ independently represent hydrogen, halogen,amino, mono- or di(lower alkyl)amino, lower alkanoylamino, nitro, cyano,substituted or unsubstituted lower alkyl, hydroxy, lower alkoxy, loweralkylthio, carboxy, lower alkoxycarbonyl, lower alkanoyl, aralkyloxy, orlower alkanoyloxy; R⁶, R⁷, R⁸, and R⁹ independently represent hydrogen,hydroxy, substituted or unsubstituted lower alkoxy, or aralkyloxy, orany adjoining two of them are combined to form methylenedioxy; R¹⁰represents hydrogen or lower alkyl; and Y and Z independently representN or C--R¹¹ (wherein R¹¹ represents hydrogen, substituted orunsubstituted lower alkyl, or halogen), or a pharmaceutically acceptablesalt thereof.

The present invention also relates to a method for protecting myocardiumor preventing or treating inflammatory edema and a method for preventingor treating diseases caused by adenosine uptake, which compriseadministering an effective amount of a1,2,3,4-tetrahydro-2,4-dioxoquinazoline derivative represented byformula (I) or a pharmaceutically acceptable salt thereof.

The present invention further relates to the use of a1,2,3,4-tetrahydro-2,4-dioxoquinazoline derivative represented byformula (I) or a pharmaceutically acceptable salt thereof for thepreparation of a pharmaceutical composition which is useful for theprotection of myocardium, the prevention or treatment of inflammatoryedema, and the prevention or treatment of diseases caused by adenosineuptake.

Furthermore, the present invention relates to the use of a1,2,3,4-tetrahydro-2, 4-dioxoquinazoline derivative represented byformula (I) or a pharmaceutically acceptable salt thereof for theprotection of myocardium, the prevention or treatment of inflammatoryedema, and the prevention or treatment of diseases caused by adenosineuptake.

The present invention also provides a1,2,3,4-tetrahydro-2,4-dioxoquinazoline derivative represented byformula (I-a): ##STR3## wherein R^(1a) represents substituted orunsubstituted lower alkyl, alkenyl, or substituted or unsubstitutedaralkyl; and R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, Y and Z have the samemeanings as defined above, and a pharmaceutically acceptable saltthereof.

The compounds represented by formula (I) and the compounds representedby formula (I-a) are hereinafter referred to as Compounds (I) andCompounds (I-a), respectively. The same applies to the compounds ofother formula numbers.

In the definitions of the groups in formula (I) and formula (I-a), thelower alkyl and the lower alkyl moiety of the mono- or di(loweralkyl)amino, lower alkanoylamino, lower alkoxy, lower alkylthio, loweralkoxycarbonyl, lower alkanoyl and lower alkanoyloxy mean astraight-chain or branched alkyl group having 1 to 8 carbon atoms, suchas methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, hexyl, heptyl, and octyl. The alkenylmeans a straight-chain or branched alkenyl group having 2 to 6 carbonatoms, such as vinyl, allyl, methacryl, crotyl, 3-butenyl, 2-pentenyl,4-pentenyl, 2-hexenyl, and 5-hexenyl. The aralkyl and the aralkyl moietyof the aralkyloxy mean an aralkyl group having 7 to 13 carbon atoms,such as benzyl, phenethyl, and benzhydryl. The halogen includesfluorine, chlorine, bromine, and iodine.

The substituted lower alkyl and the substituted lower alkoxy each has 1to 3 independently selected substituents. Examples of the substituentsare halogen, nitro, cyano, hydroxy, lower alkoxy, carboxy, loweralkoxycarbonyl, lower alkanoyl, cycloalkyl, amino, mono- or di(loweralkyl)amino, and phthalimide. The substituted aralkyl has 1 to 3independently selected substituents on the benzene ring thereof.Examples of the substituents are halogen, lower alkyl, nitro, cyano,amino, mono- or di(lower alkyl)amino, hydroxy, lower alkoxy, carboxy,lower alkoxycarbonyl, lower alkanoyl, methylenedioxy, andtrifluoromethyl.

In the definitions of the substituents, the halogen, lower alkoxy, loweralkoxycarbonyl, lower alkanoyl, mono- or di(lower alkyl)amino, and loweralkyl have the same meanings as defined above. The cycloalkyl means acycloalkyl group having 3 to 8 carbon atoms, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The pharmaceutically acceptable salts of Compounds (I) and Compounds(I-a) include pharmaceutically acceptable acid addition salts, metalsalts, ammonium salts, organic amine addition salts, and amino acidaddition salts.

Examples of the pharmaceutically acceptable acid addition salts ofCompounds (I) and Compounds (I-a) are inorganic acid addition salts suchas hydrochloride, sulfate, and phosphate, and organic acid additionsalts such as acetate, maleate, fumarate, tartrate, citrate, andmethanesulfonate. Examples of the pharmaceutically acceptable metalsalts are alkali metal salts such as sodium salt and potassium salt,alkaline earth metal salts such as magnesium salt and calcium salt,aluminum salt, and zinc salt. Examples of the pharmaceuticallyacceptable ammonium salts are ammonium salt and tetramethylammoniumsalt. Examples of the pharmaceutically acceptable organic amine additionsalts are salts with morpholine and piperidine. Examples of thepharmaceutically acceptable amino acid addition salts are salts withlysine, glycine, and phenylalanine.

The processes for producing Compounds (I) are described below.

Process 1: Process for producing Compound (I-b) [Compound (I) in whichR¹ is hydrogen]

Compound (I-b) can be prepared by the following reaction steps: ##STR4##(In the formulae, X^(a) represents chlorine, bromine, iodine,methanesulfonyloxy, benzenesulfonyloxy, or toluenesulfonyloxy; and R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, Y, and Z have the same meanings asdefined above.)

The starting Compound (II) can be obtained according to the methoddescribed in Chem. Pharm. Bull., 34, 1907-1916 (1986).

(Step 1)

The ethoxycarbonyl group of Compound (II) is hydrolyzed in the presenceof an acid, such as sulfuric acid, hydrochloric acid, or hydrobromicacid, in an appropriate solvent, such as water, a lower alcohol, e.g.,methanol, ethanol, or isopropanol, a cyclic ether, e.g., tetrahydrofuran(THF) or 1,4-dioxane, or a mixture thereof, at a temperature of roomtemperature to the boiling point of the solvent used for 10 minutes to48 hours. Then, Compound (I-b) can be obtained by reaction of thehydrolysis product with Compound (III) [South African Patent No. 6706512 (1968); Chem. Pharm. Bull., 38, 2179-2183 (1990)] in the presenceof a base, such as a tertiary amine, e.g., triethylamine or pyridine, oran alkali metal carbonate, e.g., sodium carbonate or potassiumcarbonate, in an appropriate solvent, such as a lower alcohol, e.g.,methanol, ethanol or isopropanol, a cyclic ether, e.g., THF or1,4-dioxane, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), or amixture thereof, at a temperature of room temperature to the boilingpoint of the solvent used for 10 minutes to 48 hours according to themethod described in Chem. Pharm. Bull., 38, 1591-1595 (1990) or Chem.Pharm. Bull., 38, 2179-2183 (1990).

Process 2: Process for producing Compound (I-a) [Compound (I) in whichR¹ is substituted or unsubstituted lower alkyl, alkenyl, or substitutedor unsubstituted aralkyl]

Compound (I-a) can be prepared by the following reaction step. ##STR5##(In the formulae, X^(b) represents chlorine, bromine, iodine,methanesulfonyloxy, benzenesulfonyloxy, or toluenesulfonyloxy; andR^(la), R², R³, R⁴ l , R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, Y, and Z have the samemeanings as defined above.)

(Step 2)

Compound (I-a) can be obtained by reaction of Compound (I-b) with 1 to 2equivalents of Compound (IV) in the presence of 1 to 2 equivalents of abase, such as sodium hydride, potassium carbonate, or cesium carbonate,in an inert solvent, such as THF, DMF, acetone, or methyl ethyl ketone,at a temperature of 0° C. to the boiling point of the solvent used for10 minutes to 24 hours.

Compound (I-a) can also be prepared by the following reaction steps:##STR6## (In the formulae, X^(a), X^(b), R^(1a), R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, Y, and Z have the same meanings as defined above)

(Step 3)

Compound (I-a) can be obtained by preparing Compound (V) from Compound(II) by the similar method as in Step 2 and then treating Compound (V)in the similar manner as in Step 1.

Compound (I) having at least one amino, mono- or di(lower alkyl)amino,or lower alkanoylamino group as R², R³, R⁴, or R⁵ can also be preparedby reducing a corresponding Compound (I) having a nitro group as R², R³,R⁴, or R⁵, and if necessary, alkylating or acylating the product. Thereduction can be carried out in a conventional manner, for example, bycatalytic reduction or reduction using a metal. The catalytic reductionis usually carried out in the presence of a catalyst, such as Raneynickel, palladium on carbon, or platinum oxide, in an appropriatesolvent, such as methanol, ethanol, ethyl acetate, dioxane, THF, oracetic acid, at room temperature under an atmospheric pressure for 10minutes to 48 hours. The reduction using a metal can be carried out in azinc-acetic acid system, an iron-acetic acid system, an iron-ferricchloride-ethanol-water system, an iron-hydrochloric acid system, atin-hydrochloric acid system, or the like, at a temperature of roomtemperature to the boiling point of the solvent used for 10 minutes to48 hours. The alkylation or acylation of the reduction product iscarried out by using a common alkylating agent (such as an alkyl halide,e.g., methyl iodide) or acylating agent (such as an acid anhydride,e.g., acetic anhydride, or an acid halide, e.g., acetyl chloride), ifnecessary in the presence of a base, such as pyridine, triethylamine, analkyl metal hydroxide, or an alkyl metal carbonate, and/or a solvent,such as chloroform, dichloromethane, THF, or 1,4-dioxane, at atemperature of 0° C. to the boiling point of the solvent used for 10minutes to 48 hours.

Compound (I) having at least one hydroxy-substituted alkyl group as R²,R³, R⁴, or R⁵ can also be prepared by reducing or alkylating acorresponding Compound (I) having an alkanoyl-substituted alkyl group asR², R³, R⁴ or R⁵. The reduction can be carried out by using a reducingagent, such as lithium aluminum hydride or sodium boron hydride, in anappropriate solvent, such as methanol, ethanol, ethyl acetate, dioxaneor THF, usually at a temperature of -78° C. to room temperature for 10minutes to 48 hours. The alkylation is carried out by using a commonorganometallic reagent, such as a Grignard reagent, e.g.,methylmagnesium bromide or ethylmagnesium chloride, or an organolithiumreagent, e.g., methyl lithium or butyl lithium, in an appropriatesolvent, such as dioxane, ether, or THF, usually at a temperature of-78° C. to room temperature for 10 minutes to 48 hours.

Compound (I) having at least one carboxyl group as R², R³, R⁴, or R⁵ canalso be prepared by subjecting a corresponding Compound (I) having anacetyl group as R², R³, R⁴, or R⁵ to haloform reaction. The haloformreaction can be carried out by using a solution of sodium hypohalogeniteprepared from chlorine or bromine and an aqueous solution of sodiumhydroxide according to the method described in J. Am. Chem. Soc., 72,1642 (1950) or the like.

Compound (I) having at least one hydroxyl group as R⁶, R⁷, R⁸, or R⁹ canalso be prepared by subjecting a corresponding Compound (I) having abenzyloxy group as R⁶, R⁷, R⁸, or R⁹ to the above-mentioned catalyticreduction.

Compound (I) having at least one hydroxyl group as R², R³, R⁴ or R⁵ ; orR⁶, R⁷, R⁸ or R⁹ can also be prepared by dealkylating a correspondingCompound (I) having a lower alkoxy group as R², R³, R⁴ or R⁵ ; or R⁶,R⁷, R⁸, or R⁹. The dealkylation can be carried out in the presence of anacid, such as hydrobromic acid or hydroiodic acid, with or without asolvent, such as water, acetic acid, or a lower alcohol, e.g., methanolor ethanol; or in the presence of at least an equivalent amount of analkali metal salt (e.g., a sodium salt or a potassium salt) of a thiolcompound, e.g., ethanethiol or thiophenol, in a solvent, such as DMF orDMSO; or in the presence of a Lewis acid, such as boron trichloride,boron tribromide, or aluminum trichloride, in a solvent, such asdichloromethane. The reaction is carried out at a temperature of roomtemperature to the boiling point of the solvent used and is completed in30 minutes to 48 hours.

Compound (I) having at least one lower alkoxy group as R², R³, R⁴, or R⁵; or R⁶, R⁷, R⁸, or R⁹ can also be prepared from a correspondingCompound (I) having a hydroxyl group as R², R³, R⁴ or R⁵ ; or R⁶, R⁷,R⁸, or R⁹ by the similar method as in Step 2.

Compound (I) having hydrogen as R¹⁰ can also be prepared by subjecting acorresponding Compound (I) having halogen as R¹⁰ to the above-mentionedcatalytic reduction.

The intermediates and desired compounds in the above-described processescan be isolated and purified by purification methods conventionally usedin organic synthetic chemistry, for example, neutralization, filtration,extraction, drying, concentration, recrystallization, and various kindsof chromatography. The intermediates may be subjected to the subsequentreaction without being purified.

In the case where a salt of Compound (I) is desired and it is producedin the form of the desired salt, it can be subjected to purification assuch. In the case where Compound (I) is produced in the free state andits salt is desired, Compound (I) is dissolved or suspended in asuitable organic solvent, followed by addition of an acid or a base toform a salt.

Compounds (I) and pharmaceutically acceptable salts thereof may be inthe form of adducts with water or various solvents, which can also beused as the drugs of the present invention.

Examples of Compounds (I) obtained by the above-described processes areshown in Tables 1 to 5.

                                      TABLE 1                                     __________________________________________________________________________     ##STR7##                                                                     Compd. No.                                                                           R.sup.1        R.sup.2                                                                          R.sup.3                                                                              R.sup.4                                                                           R.sup.5                                   __________________________________________________________________________    1      CH.sub.3       H  NO.sub.2                                                                             H   H                                         2      CH.sub.2 CH.sub.3                                                                            H  NO.sub.2                                                                             H   H                                         3      (CH.sub.2).sub.2 CH.sub.3                                                                    H  NO.sub.2                                                                             H   H                                         4      (CH.sub.2).sub.3 CH.sub.3                                                                    H  NO.sub.2                                                                             H   H                                         5      CH.sub.2 CHCH.sub.2                                                                          H  NO.sub.2                                                                             H   H                                         6      CH.sub.2 CO.sub.2 CH.sub.2 CH.sub.3                                                          H  NO.sub.2                                                                             H   H                                         7      CH.sub.2 CN    H  NO.sub.2                                                                             H   H                                                 ##STR8##      H  NO.sub.2                                                                             H   H                                         9                                                                                     ##STR9##      H  NO.sub.2                                                                             H   H                                         10                                                                                    ##STR10##     H  NO.sub.2                                                                             H   H                                         11                                                                                    ##STR11##     H  NO.sub.2                                                                             H   H                                         12                                                                                    ##STR12##     H  NO.sub.2                                                                             H   H                                         13                                                                                    ##STR13##     H  NO.sub.2                                                                             H   H                                         14     CH.sub.3       H  NH.sub.2                                                                             H   H                                         15     CH.sub.3       H  H      H   Cl                                        16     CH.sub.2 CH.sub.3                                                                            H  CH.sub.3                                                                             H   H                                         17     (CH.sub.2).sub.2 CH.sub.3                                                                    H  CH.sub.3                                                                             H   H                                         18     CH.sub.3       H  NO.sub.2                                                                             H   Cl                                        25     CH.sub.2 CH(CH.sub.3).sub.2                                                                  H  NO.sub.2                                                                             H   H                                         26                                                                                    ##STR14##     H  NO.sub.2                                                                             H   H                                         27                                                                                    ##STR15##     H  NO.sub.2                                                                             H   H                                         28     CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                          H  NO.sub.2                                                                             H   H                                         29     CH.sub.2 CH.sub.2 NH.sub.2                                                                   H  NO.sub.2                                                                             H   H                                         30     (CH.sub.2).sub.3 NH.sub.2                                                                    H  NO.sub.2                                                                             H   H                                         31     CH(CH.sub.3).sub.2                                                                           H  NO.sub.2                                                                             H   H                                         32     CH(CH.sub.3)CH.sub.2 CH.sub.3                                                                H  NO.sub.2                                                                             H   H                                         33                                                                                    ##STR16##     H  NO.sub.2                                                                             H   H                                         34                                                                                    ##STR17##     H  NO.sub.2                                                                             H   H                                         35     CH.sub.2 CH.sub.3                                                                            H  H      H   Cl                                        36     CH.sub.2 CH.sub.3                                                                            H  NO.sub.2                                                                             Cl  H                                         37     CH.sub.2 CH.sub.3                                                                            H  NO.sub.2                                                                             H   Cl                                        38     (CH.sub.2).sub.2 CH.sub.3                                                                    H  NO.sub.2                                                                             H   Cl                                        39     CH.sub.2 CH.sub.3                                                                            H  NO.sub.2                                                                             H   NO.sub.2                                  40     CH.sub.3       H  Cl     H   H                                         41     CH.sub.2 CH.sub.3                                                                            H  Cl     H   H                                         42     (CH.sub.2).sub.2 CH.sub.3                                                                    H  Cl     H   H                                         43     CH.sub.2 CH.sub.3                                                                            H  Cl     H   NO.sub.2                                  44     (CH.sub.2).sub.2 CH.sub.3                                                                    H  Cl     H   NO.sub.2                                  45     CH.sub.3       H  Br     H   H                                         46     CH.sub.2 CH.sub.3                                                                            H  Br     H   H                                         47     CH.sub.2 CH.sub.3                                                                            H  Br     Cl  H                                         48     CH.sub.2 CH.sub.3                                                                            H  Br     H   Br                                        49     CH.sub.2 CH.sub.3                                                                            H  H      Cl  H                                         50     CH.sub.3       H  CH.sub.3                                                                             H   H                                         51     (CH.sub.2).sub.3 CH.sub.3                                                                    H  CH.sub.3                                                                             H   H                                         52     (CH.sub.2).sub.4 CH.sub.3                                                                    H  CH.sub.3                                                                             H   H                                         53     CH.sub.2 CHCH.sub.2                                                                          H  CH.sub.3                                                                             H   H                                         54     CH.sub.3       H  CH.sub.2 CH.sub.3                                                                    H   H                                         55     CH.sub.3       H  (CH.sub.2).sub.2 CH.sub.3                                                            H   H                                         56     CH.sub.3       H  CH(CH.sub.3).sub.2                                                                   H   H                                         57     CH.sub.3       CH.sub.3                                                                         H      H   H                                         58     (CH.sub.2).sub.2 CH.sub.3                                                                    CH.sub.3                                                                         H      H   H                                         59     CH.sub.3       H  H      H   CH.sub.3                                  60     CH.sub.3       H  CH(OH)CH.sub.3                                                                       H   H                                         61     CH.sub.3       H  C(CH.sub.3).sub.2 OH                                                                 H   H                                         62     CH.sub.3       H  CO.sub.2 H                                                                           H   H                                         63     CH.sub.3       H  COCH.sub.3                                                                           H   H                                         64     CH.sub.2 CH.sub.3                                                                            H  NH.sub.2                                                                             H   H                                         65     CH.sub.2 CH.sub.3                                                                            H  NHCOCH.sub.3                                                                         H   H                                         66     CH.sub.2 CH.sub.3                                                                            H  OH     H   H                                         67     (CH.sub.2).sub.2 CH.sub.3                                                                    H  OH     H   H                                         68     CH.sub.3       H  H      OH  H                                         69     CH.sub.3       H  OCH.sub.3                                                                            H   H                                         70     CH.sub.2 CH.sub.3                                                                            H  OCH.sub.3                                                                            H   H                                         71     (CH.sub.2).sub.2 CH.sub.3                                                                    H  OCH.sub.3                                                                            H   H                                         72     CH.sub.2 CH.sub.3                                                                            H  OCH.sub.2 CH.sub.3                                                                   H   H                                         73     (CH.sub.2).sub.2 CH.sub.3                                                                    H  O(CH.sub.2).sub.2 CH.sub.3                                                           H   H                                         74     CH.sub.3       H  H      OCH.sub.3                                                                         H                                         __________________________________________________________________________

                  TABLE 2                                                         ______________________________________                                         ##STR18##                                                                    Compd. No.                                                                              R.sup.1   R.sup.3 Y          Z                                      ______________________________________                                        75        CH.sub.3  CH.sub.3                                                                              N          N                                      76        CH.sub.3  CH.sub.3                                                                              N          CCl                                    77        CH.sub.3  CH.sub.3                                                                              N          CH                                     78        CH.sub.3  CH.sub.3                                                                              CCl        N                                      79        CH.sub.2 CH.sub.3                                                                       NO.sub.2                                                                              CCl        N                                      80        CH.sub.3  CH.sub.3                                                                              CCH.sub.3  N                                      81        CH.sub.2 CH.sub.3                                                                       NO.sub.2                                                                              CCH.sub.3  N                                      82        CH.sub.3  CH.sub.3                                                                              CCH.sub.2 CH.sub.2 CH.sub.3                                                              N                                      83        CH.sub.3  CH.sub.3                                                                              CCH(CH.sub.3).sub.2                                                                      N                                      ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                         ##STR19##                                                                    Compd.                                                                        No.    R.sup.6                                                                             R.sup.7       R.sup.8     R.sup.9                                ______________________________________                                        84     H     OCH.sub.3     H           H                                      85     H     H             OCH.sub.3   H                                      86     H     OCH.sub.3     OCH.sub.3   OCH.sub.3                              87     H     OCH.sub.3     OCH.sub.2 C.sub.6 H.sub.5                                                                 H                                      88     H     OCH.sub.2 C.sub.6 H.sub.5                                                                   OCH.sub.2 C.sub.6 H.sub.5                                                                 H                                      89     H     OCH.sub.3     OH          H                                      90     H     OH            OCH.sub.3   H                                      91     H     OCH.sub.3     O(CH.sub.2).sub.2 CH.sub.3                                                                H                                      92     H     O(CH.sub.2).sub.2 CH.sub.3                                                                  OCH.sub.3   H                                      93     H     OCH.sub.3     OCH.sub.2 CO.sub.2 CH.sub.2 CH.sub.3                                                      H                                      94     H     OCH.sub.2 CO.sub.2 CH.sub.2 CH.sub.3                                                        OCH.sub.3   H                                      95     H     OCH.sub.3     OCH.sub.2 CO.sub.2 H                                                                      H                                      96     H     OCH.sub.3     OCH.sub.2 CH.sub.2 N(CH.sub.3).sub.2                                                      H                                      97     H     OH            OH          H                                      98     H     OCH.sub.2 CH.sub.3                                                                          OCH.sub.2 CH.sub.3                                                                        H                                      99     H     OCH.sub.2 O             H                                        ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                         ##STR20##                                                                    Compd. No.  R.sup.2  R.sup.3    R.sup.4                                                                             R.sup.5                                 ______________________________________                                        19          H        NH.sub.2   H     H                                       20          H        NHCOCH.sub.3                                                                             H     H                                       21          H        H          Cl    H                                       22          H        CH.sub.3   H     H                                       23          H        NO.sub.2   H     Cl                                      24          H        NO.sub.2   H     H                                       100         CH.sub.3 H          H     H                                       101         H        H          H     CH.sub.3                                102         H        OH         H     H                                       ______________________________________                                    

                                      TABLE 5                                     __________________________________________________________________________    Compd. No.                                                                    __________________________________________________________________________    103                                                                                   ##STR21##                                                             104                                                                                   ##STR22##                                                             105                                                                                   ##STR23##                                                             106                                                                                   ##STR24##                                                             107                                                                                   ##STR25##                                                             108                                                                                   ##STR26##                                                             __________________________________________________________________________

The pharmacological activities of typical Compounds (I) are shown belowby Test Examples.

TEST EXAMPLE 1

Inhibitory Effect on [³ H]-Adenosine Uptake

A blood sample was obtained from a healthy male adult under 40 years ofage by brachial venipuncture using a syringe containing citrate andsubjected to centrifugation to obtain washed erythrocytes. To 100 μl ofan erythrocyte suspension (2.5×10⁹ /ml) was added 100 μl of a 21% DMSOsolution of a test compound. After allowing the suspension to stand atroom temperature for 1 hour, 10 μl of a [³ H]-adenosine solution wasadded thereto. Ten seconds later, 200 μl of a dilazep solution (1 mg/ml)was added to stop the reaction. The erythrocytes were dissolved inTriton X-100, and the uptake amount of ³ H was measured with a liquidscintillation counter. The concentration of the test compound whichinhibits the [³ H]-adenosine uptake by 50% (IC₅₀) was calculated. Theresults obtained are shown in Table 6.

                  TABLE 6                                                         ______________________________________                                                     [.sup.3 H]-Adenosine                                             Compound     Uptake Inhibition                                                No.          IC.sub.50 (nM)                                                   ______________________________________                                        1            42                                                               2            103                                                              3            62                                                               6            462                                                              8            295                                                              24           38                                                               45           54                                                               50           54                                                               55           171                                                              63           88                                                               69           157                                                              80           127                                                              ______________________________________                                    

TEST EXAMPLE 2

Inhibitory Effect on [³ H]-Nitrobenzylthioinosine (NBI) Binding (anindication of adenosine uptake inhibitory activity)

The cerebral cortex of a male guinea pig of Hartley strain washomogenized with an ice-cooled 50 mM tris-HCl buffer (pH 7.4) in anamount of 25 times (w/v) that of the tissue. The homogenate wascentrifuged (30,000× g, 4° C., 20 mins.), and the supernatant wasdiscarded. To the precipitate was added the same amount of the buffer,followed by homogenization and then centrifugation in the same manner asabove. The obtained precipitate was suspended in 20 times as much bufferas the precipitate to prepare a suspension for testing.

To a DMSO solution of a test compound were added 1.5 nM of [³ H]-NBI and5 mg (wet basis) of the tissue homogenate, and the mixture was allowedto stand at 25° C. for 30 minutes. To the mixture was added 4 ml of anice-cooled buffer, followed by rapid filtration with suction through aglass filter (GF/C, produced by Whatman Ltd.) or a Ready filter(produced by Beckman Co.) to stop the reaction. The filter wastransferred to a scintillation vial, and after drying, Scintisol EX-Hwas added thereto. The radioactivity was measured with a liquidscintillation counter. The binding inhibitory activity was expressed interms of an inhibition constant (Ki value) as calculated according toCheng-Prusoff's formula. The results obtained are shown in Table 7below.

                  TABLE 7                                                         ______________________________________                                        Compound     [.sup.3 H]-NBI Binding                                           No.          Ki Value (nM)                                                    ______________________________________                                        1            18                                                               2            18                                                               3            4.3                                                              24           15                                                               45           6.9                                                              50           12                                                               69           11                                                               ______________________________________                                    

TEST EXAMPLE 3

Inhibitory Effect on Ischemic Paw Edema in Mice

Ischemia followed by reperfusion in the limb of a mouse induces pawedema due to membrane injury in which active oxygen is involved[Arzneim.-Forsch., 41, 469-474 (1991)]. In general, peroxidation ofmembrane lipid and calcium influx into cells play roles inischemia-reperfusion injury [Life Science, 29, 1289-1295 (1981); JapanJ. Pharmacol., 52, 553-562 (1990)]. It is active oxygen production thattriggers these factors, and the source of active oxygen includesendothelial cells and leukocytes [J. Mol. Cell Cardiol., 20 (Suppl. II),55-63 (1988); Blood, 73, 301-306 (1989)]. As possible mechanisms forsuppression of paw edema development, inhibition of activation ofleukocytes by adenosine which has increased in the ischemic site,inhibition of active oxygen production which is accompanied byactivation of leukocytes, and inhibition of calcium overload due to thecyclic AMP increasing activity of adenosine have been suggested [Am. J.Physiol., 257, H1334-1339 (1989); J. Immunol., 135, 1366-1371 (1985)].Accordingly, it is believed that a compound effective on an ischemicpodedema model in mice as hereinafter described would provide aconvenient and useful model for evaluating an adenosine uptakeinhibitor.

Experiments were conducted in accordance with the method described inArzneim.-Forsch., 41, 469-474 (1991). A test compound was suspended inwater and orally given to grouped male mice of ddY-strain weighing 25 to30 g at a dose of 30 mg/kg. One hour later, the left hind limb was boundwith a rubber band for 20 minutes to cause ischemia, and 20, 40 and 60minutes after blood recirculation, the paw thickness was measured with apair of calipers (Digimatic Caliper manufactured by Mitsutoyo K.K.). Thepaw edema was determined as the difference in thickness between the lefthind paw (ischemia-treated) and the non-treated right one. Each resultwas expressed in terms of percent suppression of edema in a testcompound group on the basis of the edema in a control group. The resultsobtained are shown in Table 8 below.

                  TABLE 8                                                         ______________________________________                                                Paw Edema Supression Rate (%)                                         Compound  After       After     After                                         No.       20 minutes  40 minutes                                                                              60 minutes                                    ______________________________________                                        2         4.1 ± 2.98                                                                              9.0 ± 3.79                                                                          15.5 ± 4.09                                3         4.8 ± 4.40                                                                             11.6 ± 2.68                                                                          14.9 ± 3.58                                ______________________________________                                    

TEST EXAMPLE 4

Acute Toxicity Test

A test compound was intraperitoneally or orally administered to groupsof ddY-strain male mice weighing 20±1 g, each group consisting of threemice. Seven days after the administration, the mortality was observed toobtain a minimum lethal dose (MLD) of the compound. The results obtainedare shown in Table 9 below.

                  TABLE 9                                                         ______________________________________                                        Compound        MLD (mg/kg)                                                   No.             p.o.    i.p.                                                  ______________________________________                                        2               >300    >100                                                  3               >300    >100                                                  ______________________________________                                    

Compounds (I) and pharmaceutically acceptable salts thereof can beformulated into generally employed dose forms, such as tablets,capsules, syrups, injections, drips, and suppositories, and administeredorally or parenterally through intramuscular injection, intravenousinjection, intraarterial injection, drip infusion, or rectaladministration using suppositories. For preparing these dose forms fororal or parenteral administration, generally known techniques areapplied. For example, the preparations may contain various excipients,lubricants, binders, disintegrating agents, suspending agents,isotonizing agents, emulsifiers, and the like.

Examples of the carriers which can be used are water, injectabledistilled water, physiological saline, glucose, fructose, sucrose,mannitol, lactose, starch, cellulose, methyl cellulose, carboxymethylcellulose, hydroxypropyl cellulose, alginic acid, talc, sodium citrate,calcium carbonate, calcium hydrogenphosphate, magnesium stearate, urea,silicone resins, sorbitan fatty acid esters, and glycerin fatty acidesters.

The dose varies depending upon the mode of administration, the age, bodyweight, and conditions of a patient, etc. However, generally, Compound(I) or a pharmaceutically acceptable salt thereof is administered in adose of 1 to 900 mg/60 kg/day either orally or parenterally.

Certain embodiments of the present invention are illustrated in thefollowing Examples and Reference Examples.

BEST MODE FOR CARRYING OUT THE INVENTION EXAMPLE 1

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1-methyl-6-nitro-2,4-dioxo-quinazoline(Compound 1)

In 1 ml of DMF was dissolved 239 mg (0.5 mmol) of3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline(Compound 24) obtained in Reference Example 6, and the solution wasadded dropwise to a solution of 22 mg (0.55 mmol) of 60% sodium hydridein 2 ml of DMF under ice cooling. After stirring for 20 minutes, 0.031ml (0.5 mmol) of methyl iodide was added thereto, followed by stirringat room temperature for 1 hour. A saturated aqueous solution of ammoniumchloride was added to the reaction mixture, and the precipitated solidwas collected by filtration. The solid was washed with water, dried byheating, and recrystallized from ethanol/ether to give 152.9 mg (yield:62%) of Compound 1 as pale yellow crystals.

¹ H-NMR (CDCl₃) δ(ppm): 9.08 (d, 1H, J=2.5 Hz), 8.70 (s, 1H), 8.51 (dd,1H, J=9.0, 2.5 Hz), 7.32 (d, 1H, J=9.0 Hz), 7.27 (s, 1H), 7.18 (s, 1H),5.31-5.23 (m, 1H), 4.37-4.32 (br.-d, 2H), 4.04 (s, 3H), 4.02 (s, 3H),3.67 (s, 3H), 3.25-3.16 (br.-t, 2H), 3.09-2.96 (m, 2H), 1.88-1.83(br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1710, 1664, 1612, 1504, 1330.

Melting Point (ethanol-ether): 286°-287° C. (decomposition)

EXAMPLE 2

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1-ethyl-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline(Compound 2)

The procedure similar to that described in Example 1 was repeated,except that 300 mg (0.63 mmol) of Compound 24 was used and ethyl iodidewas used in place of methyl iodide. As a result, 213.1 mg (yield: 67%)of Compound 2 was obtained as pale yellow crystals.

¹ H-NMR (CDCl₃) δ(ppm): 9.09 (d, 1H, J=2.5 Hz), 8.69 (s, 1H), 8.51 (dd,1H, J=9.0, 2.5 Hz), 7.32 (d, 1H, J=9.0 Hz), 7.29 (s, 1H), 7.18 (s, 1H),5.31-5.22 (m, 1H), 4.39-4.34 (br. -d, 2H), 4.25 (q, 2H, J=7.5 Hz), 4.04(s, 3H), 4.02 (s, 3H), 3.26-3.16 (br.-t, 2H), 3.10-2.96 (m, 2H),1.89-1.84 (br.-d, 2H), 1.40 (t, 3H, J=7.5 Hz).

IR (KBr tab.) (cm⁻¹): 1713, 1657, 1610, 1505, 1323.

Melting Point (ether): 267°-268° C.

EXAMPLE 3

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-nitro-2,4-dioxo-1-propyl-quinazoline(Compound 3)

The procedure similar to that described in Example 1 was repeated,except that 300 mg (0.63 mmol) of Compound 24 was used and propyl iodidewas used in place of methyl iodide. As a result, 209.9 mg (yield: 64%)of Compound 3 was obtained as pale yellow crystals.

¹ H-NMR (CDCl₃) δ(ppm): 9.09 (d, 1H, J=2.5 Hz), 8.70 (s, 1H), 8.49 (dd,1H, J=9.0, 2.5 Hz), 7.29 (d, 1H, J=9.0 Hz), 7.29 (s, 1H), 7.18 (s, 1H),5.30-5.20 (m, 1H), 4.37-4.32 (br. -d, 2H), 4.12 (dist.-t, 2H), 4.04 (s,3H), 4.02 (s, 3H), 3.25-3.16 (br.-t, 2H), 3.10-2.96 (m, 2H), 1.88-1.76(m, 4H), 1.07 (t, 3H, J=7.5 Hz).

IR (KBr tab.) (cm⁻¹): 1713, 1667, 1613, 1499, 1450, 1326.

Melting Point (ether): 234°-236° C.

EXAMPLE 4

1-Butyl-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-nitro-2,4-dioxo-quinazoline(Compound 4)

The procedure similar to that described in Example 1 was repeated,except that 334.6 mg (0.7 mmol) of Compound 24 was used and butyl iodidewas used in place of methyl iodide. As a result, 228.9 mg (yield: 61%)of Compound 4 was obtained as pale yellow crystals.

¹ H-NMR (CDCl₃) δ(ppm): 9.09 (d, 1H, J=2.5 Hz), 8.69 (s, 1H), 8.50 (dd,1H, J=9.0, 2.5 Hz), 7.32 (d, 1H, J=9.0 Hz), 7.26 (s, 1H), 7.18 (s, 1H),5.32-5.23 (m, 1H), 4.43-4.38 (br.-d, 2H), 4.18-4.12 (dist.-t, 2H), 4.05(s, 3H), 4.02 (s, 3H), 3.28-3.19 (br.-t, 2H), 3.08-2.96 (m, 2H),1.89-1.84 (br.-d, 2H), 1.7 6-1.68 (m, 2H), 1.56-1.45 (m, 2H), 1.03 (t,3H, J=7.5 Hz).

IR (KBr tab.) (cm⁻¹): 1716, 1673, 1616, 1505, 1453, 1332.

Melting Point (ethyl acetate-ether): 194°-195° C.

EXAMPLE 5

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-nitro-2,4-dioxo-1-(2-propenyl)-quinazoline(Compound 5)

The procedure similar to that described in Example 1 was repeated,except that 334.6 mg (0.7 mmol) of Compound 24 was used and allylbromide was used in place of methyl iodide. As a result, 192.8 mg(yield: 53%) of Compound 5 was obtained as pale yellow crystals.

¹ H-NMR (CDCl₃) δ(ppm): 9.09 (d, 1H, J=2.5 Hz), 8.69 (s, 1H), 8.47 (dd,1H, J=9.0, 2.5 Hz), 7.30 (s, 1H), 7.29 (d, 1H, J=9.0 Hz), 7.18 (s, 1H),5.94 (ddt, 1H, J=17, 10, 5 Hz), 5.37-5.22 (m, 3H), 4.82 (d, 2H, J=5 Hz),4.41-4.36 (br.-d, 2H), 4.04 (s, 3H), 4.02 (s, 3H), 3.27-3.18 (br.-t,2H), 3.10-2.97 (m, 2H), 1.90-1.85 (br. -d, 2H).

IR (KBr tab.) (cm⁻¹): 1720, 1672, 1616, 1504, 1468, 1428, 1337.

Melting Point (ethyl acetate-ether): 225°-226° C.

EXAMPLE 6

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1-ethoxycarbonylmethyl-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline(Compound 6)

The procedure similar to that described in Example 1 was repeated,except that 300 mg (0.63 mmol) of Compound 24 was used and ethylbromoacetate was used in place of methyl iodide. As a result, 61.3 mg(yield: 17%) of Compound 6 was obtained as pale yellow crystals.

¹ H-NMR (CDCl₃) δ(ppm): 9.10 (d, 1H, J=2.5 Hz), 8.66 (s, 1H), 8.49 (dd,1H, J=9.0, 2.5 Hz), 7.26 (s, 1H), 7.16 (s, 1H), 7.08 (d, 1H, J=9.0 Hz),5.37-5.22 (m, 1H), 4.92 (s, 2H), 4.54-4.49 (br.-d, 2H), 4.29 (q, 2H,J=7.5 Hz), 4.07 (s, 3H), 4.01 (s, 3H), 3.35-3.28 (br.-t, 2H), 3.01-2.95(m, 2H), 1.95-1.90 (br.-d, 2H), 1.33 (t, 3H, J=7.5 Hz).

IR (KBr tab.) (cm⁻¹): 1719, 1671, 1618, 1509, 1468, 1336, 1216.

Melting Point (ether): 201°-202° C.

EXAMPLE 7

1-Cyanomethyl-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-nitro-2,4-dioxo-quinazoline(Compound 7)

The procedure similar to that described in Example 1 was repeated,except that 300 mg (0.63 mmol) of Compound 24 was used andbromoacetonitrile was used in place of methyl iodide. As a result, 87.3mg (yield: 27%) of Compound 7 was obtained as pale yellow crystals.

¹ H-NMR (CDCl₃) δ(ppm): 9.13 (d, 1H, J=2.5 Hz), 8.67 (s, 1H), 8.62 (dd,1H, J=9.0, 2.5 Hz), 7.38 (d, 1H, J=9.0 Hz), 7.26 (s, 1H), 7.15 (s, 1H),5.36-5.26 (m, 1H), 5.15 (s, 2H), 4.57-4.52 (br.-d, 2H), 4.07 (s, 3H),4.02 (s, 3H), 3.37-3.27 (br.-t, 2H), 2.98-2.94 (m, 2H), 2.00-1.94(br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 2250, 1719, 1676, 1614, 1339.

Melting Point (ether): 261°-262° C.

EXAMPLE 8

1-Benzyl-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-nitro-2,4-dioxo-quinazoline(Compound 8)

The procedure similar to that described in Example 1 was repeated,except that 200 mg (0.42 mmol) of Compound 24 was used and benzylbromide was used in place of methyl iodide. As a result, 190.5 mg(yield: 80%) of Compound 8 was obtained as pale yellow crystals.

¹ H-NMR (CDCl₃) δ(ppm): 9.08 (d, 1H, J=2.5 Hz), 8.66 (s, 1H), 8.47 (dd,1H, J=9.0, 2.5 Hz), 7.49-7.22 (m, 7H), 7.17 (s, 1H), 5.41 (s, 2H),5.40-5.37 (m, 1H), 4.56-4.51 (br.-d, 2H), 4.06 (s, 3H), 4.01 (s, 3H),3.37-3.28 (br.-t, 2H), 3.11-2.98 (m, 2H), 1.97-1.94 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1712, 1666, 1616, 1500, 1331.

Melting Point (ether): 159°-162° C.

EXAMPLE 9

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1-(4-fluorobenzyl)-1,2,3,4-tetrahydro-6-nitro-2,4-dioxo-quinazoline(Compound 9)

The procedure similar to that described in Example 1 was repeated,except that 300 mg (0.63 mmol) of Compound 24 was used and4-fluorobenzyl chloride was used in place of methyl iodide. As a result,116.9 mg (yield: 32%) of Compound 9 was obtained as pale yellowcrystals.

¹ H-NMR (CDCl₃) δ(ppm): 9.09 (d, 1H, J=2.5 Hz), 8.67 (s, 1H), 8.40 (dd,1H, J=9.0, 2.5 Hz), 7.26-7.02 (m, 7H), 5.37 (s, 2H), 5.37-5.20 (m, 1H),4.51-4.46 (br.-d, 2H), 4.05 (s, 3H), 4.01 (s, 3H), 3.34-3.25 (br.-t,2H), 3.12-2.96 (m, 2H), 1.95-1.91 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1713, 1667, 1613, 1510, 1503, 1329.

Melting Point (ether): 240°-243° C.

EXAMPLE 10

1-(2,6-Dichlorobenzyl)-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline(Compound 10)

The procedure similar to that described in Example 1 was repeated,except that 300 mg (0.63 mmol) of Compound 24 was used and2,6-dichlorobenzyl bromide was used in place of methyl iodide. As aresult, 117.1 mg (yield: 29%) of Compound 10 was obtained as pale yellowcrystals.

¹ H-NMR (CDCl₃) δ(ppm): 9.05 (d, 1H, J=2.5 Hz), 8.68 (s, 1H), 8.33 (dd,1H, J=9.0, 2.5 Hz), 7.39-7.11 (m, 6H), 5.78 (s, 2H), 5.40-5.25 (m, 1H),4.47-4.44 (br. -d, 2H), 4.05 (s, 3H), 4.01 (s, 3H), 3.31-3.22 (br. -t,2H), 3.06-2.89 (m, 2H), 1.92-1.87 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1718, 1669, 1615, 1503, 1468, 1332.

Melting Point (ether): 231°-234° C.

EXAMPLE 11

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-nitro-1-(4-nitrobenzyl)-2,4-dioxoquinazoline(Compound 11)

The procedure similar to that described in Example 1 was repeated,except that 300 mg (0.63 mmol) of Compound 24 was used and 4-nitrobenzylbromide was used in place of methyl iodide. As a result, 145.0 mg(yield: 38%) of Compound 11 was obtained as pale yellow crystals.

¹ H-NMR (CDCl₃) δ(ppm): 9.11 (d, 1H, J=2.5 Hz), 8.68 (s, 1H), 8.40 (dd,1H, J=9.0, 2.5 Hz), 8.25 (d, 2H, J=8.5 Hz), 7.43 (d, 2H, J=8.5 Hz), 7.37(s, 1H), 7.17 (s, 1H), 7.12 (d, 1H, J=9.0 Hz), 5.50 (s, 2H), 5.38-5.28(m, 1H), 4.47-4.42 (br.-d, 2H), 4.04 (s, 3H), 4.01 (s, 3H), 3.67-3.62(br.-t, 2H), 3.32-3.01 (m, 2H), 1.94-1.90 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1714, 1666, 1617, 1332.

Melting Point (diisopropyl ether): 158°-161° C.

EXAMPLE 12

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1-(4-methoxybenzyl)-6-nitro-2,4-dioxoquinazoline(Compound 12)

The procedure similar to that described in Example 1 was repeated,except that 300 mg (0.63 mmol) of Compound 24 was used and4-methoxybenzyl chloride was used in place of methyl iodide. As aresult, 232.5 mg (yield: 62%) of Compound 12 was obtained as pale yellowcrystals.

¹ H-NMR (CDCl₃) δ(ppm): 9.08 (d, 1H, J=2.5 Hz), 8.69 (s, 1H), 8.38 (dd,1H, J=9.0, 2.5 Hz), 7.35 (s, 1H), 7.28 (d, 1H, J=9.0 Hz), 7.20 (d, 2H,J=8.9 Hz), 7.18 (s, 1H), 6.89 (d, 2H, J=8.9 Hz), 5.35 (s, 2H), 5.35-5.30(m, 1H), 4.45-4.40 (br.-d, 2H), 4.05 (s, 3H), 4.02 (s, 3H), 3.79 (s,3H), 3.31-3.22 (br.-t, 2H), 3.12-3.03 (m, 2H), 1.94-1.90 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1708, 1665, 1613, 1510, 1317.

Melting Point (ethyl acetate-ether): 236°-237° C.

EXAMPLE 13

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1-(4-methoxycarbonylbenzyl)-6-nitro-2,4-dioxoquinazoline(Compound 13)

The procedure similar to that described in Example 1 was repeated,except that 300 mg (0.63 mmol) of Compound 24 was used and4-methoxycarbonylbenzyl bromide was used in place of methyl iodide. As aresult, 101.2 mg (yield: 26%) of Compound 13 was obtained as pale yellowcrystals.

¹ H-NMR (CDCl₃) δ(ppm): 9.10 (d, 1H, J=2.5 Hz), 8.68 (s, 1H), 8.37 (dd,1H, J=9.0, 2.5 Hz), 8.04 (d, 2H, J=8.4 Hz), 7.37 (s, 1H), 7.31 (d, 2H,J=8.4 Hz), 7.17 (s, 1H), 7.15 (d, 1H, J=9.0 Hz), 5.46 (s, 2H), 5.40-5.34(m, 1H), 4.47-4.42 (br. -d, 2H), 4.04 (s, 3H), 4.01 (s, 3H), 3.91 (s,3H), 3.32-3.21 (br.-t, 2H), 3.08-3.02 (m, 2H), 1.95-1.91 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1716, 1667, 1616, 1330.

Melting Point (ethyl acetate-ether): 146°-150° C.

EXAMPLE 14

6-Amino-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1-methyl-2,4-dioxo-quinazoline(Compound 14)

In a solvent mixture of 15 ml of ethanol and 5 ml of water was dissolved500 mg (1.02 mmol) of Compound 1 obtained in Example 1, and 500 mg ofiron and a catalytic amount of ferric chloride were added thereto,followed by heating under reflux for 1 hour. The reaction mixture wasfiltered while hot by using a filter aid, and the filtrate wasconcentrated under reduced pressure. Water was added to the residue, andthe mixture was adjusted to pH 7 with an aqueous solution of sodiumbicarbonate and extracted with chloroform. The organic layer was washedand dried, and the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (eluent:chloroform/methanol=50/1) and recrystallized from ether to give 275.2 mg(yield: 63%) of Compound 14 as pale yellow crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.67 (s, 1H), 7.48 (m, 1H), 7.31 (s, 1H), 7.19(s, 1H), 7.03 (m, 2H), 5.34-5.24 (m, 1H), 4.40-4.35 (br.-d, 2H), 4.04(s, 3H), 4.01 (s, 3H), 3.55 (s, 3H), 3.25-2.99 (m, 4H), 1.88-1.83(br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 3400 (br.), 1694, 1650, 1505, 1340.

Melting Point (ether): 245°-247° C.

EXAMPLE 15

8-Chloro-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1-methyl-2,4-dioxo-quinazoline(Compound 15)

In 10 ml of 48% hydrobromic acid was dissolved 451.8 mg (1.24 mmol) of8-chloro-3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline(Compound a) obtained in Reference Example 7, and the solution washeated under reflux for 1 hour. After the solvent was distilled off,ethanol was added to the residue, and the precipitated crystals werecollected by filtration to give 119.5 mg of crude8-chloro-1,2,3,4-tetrahydro-1-methyl-2,4-dioxo-3-(4-piperidinyl)quinazolinehydrobromide. The crude product was dissolved in 10 ml of DMF, and 65 mg(0.29 mmol) of 4-chloro-6,7-dimethoxyquinazoline and 122 mg (0.87 mmol)of potassium carbonate were added thereto, followed by heating at 120°C. for 2 hours. To the reaction mixture were added water and dilutehydrochloric acid for neutralization, and the mixture was extracted withchloroform. The organic layer was washed with an aqueous solution ofsodium chloride and dried. The solvent was distilled off, and theresidue was purified by silica gel column chromatography (eluent:chloroform/methanol=50/1). Ethyl acetate and ether were added to theproduct, and the precipitated crystals were collected by filtration andwashed with ether to give 55.2 mg (yield: 8.9%) of Compound 15 as whitecrystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.68 (s, 1H), 8.14 (dd, 1H, J=8.0, 1.5 Hz), 7.67(dd, 1H, J=8.0, 1.5 Hz), 7.28 (s, 1H), 7.19 (dd, 1H, J=8.0, 8.0 Hz),7.18 (s, 1H), 5.18-5.09 (m, 1H), 4.37-4.31 (br. -d, 2H), 4.03 (s, 3H),4.01 (s, 3H), 3.83 (s, 3H), 3.33-3.21 (br.-t, 2H), 3.09-2.93 (m, 2H),1.89-1.85 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1704, 1656, 1503, 1460, 1341.

Melting Point (ether): 200°-202° C.

EXAMPLE 16

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1-ethyl-1,2,3,4-tetrahydro-6-methyl-2,4-dioxoquinazoline(Compound 16)

The procedure similar to that described in Example 15 was repeated,except that 850.0 mg (2.37 mmol) of3-(1-ethoxycarbonyl-4-piperidinyl)-1-ethyl-1,2,3,4-tetrahydro-6-methyl-2,4-dioxoquinazoline(Compound b) obtained in Reference Example 8 was used in place ofCompound a, whereby 599.0 mg of crude1-ethyl-1,2,3,4-tetrahydro-6-methyl-2,4dioxo-3-(4-piperidinyl)quinazolinehydrobromide was obtained. The product (300.0 mg) was treated in thesimilar manner as in Example 15 to give 355.4 mg (yield: 62.8%) ofCompound 16 as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.68 (s, 1H), 8.02 (d, 1H, J=1.5 Hz), 7.48 (dd,1H, J=8.4, 1.5 Hz), 7.27 (s, 1H), 7.19 (s, 1H), 7.10 (d, 1H, J=8.4 Hz),5.32-5.24 (m, 1H), 4.37-4.32 (br.-d, 2H), 4.17 (q, 2H, J=7.0 Hz), 4.03(s, 3H), 4.01 (s, 3H), 3.23-3.01 (m, 4H), 2.42 (s, 3H), 1.89-1.84 (br.-d, 2H), 1.35 (t, 3H, J=7.0 Hz).

IR (KBr tab.) (cm⁻¹): 1698, 1658, 1504, 1429, 1343.

Melting Point (DMF-water): 125°-128° C.

EXAMPLE 17

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-methyl-2,4-dioxo-1-propyl-quinazoline(Compound 17)

The procedure similar to that described in Example 15 was repeated,except that 1.067 g (2.86 mmol) of3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-6-methyl-2,4-dioxo-1-propyl-quinazoline(Compound c) obtained in Reference Example 9 was used in place ofCompound a, whereby 717.2 mg of crude1,2,3,4-tetrahydro-6-methyl-2,4-dioxo-3-(4-piperidinyl)-1-propylquinazolinehydrobromide was obtained. The product (300.0 mg) was treated in thesimilar manner as in Example 15 to give 322.6 mg (yield: 56.6%) ofCompound 17 as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.68 (s, 1H), 8.02 (d, 1H, J=1.5 Hz), 7.47 (dd,1H, J=8.4, 1.5 Hz), 7.26 (s, 1H), 7.19 (s, 1H), 7.06 (d, 1H, J=8.4 Hz ),5.32-5.23 (m, 1H), 4.36-4.32 (br. -d, 2H), 4.08-3.97 (dist .-t, 2H),4.03 (s, 3H), 4.01 (s, 3H), 3.23-3.00 (m, 4H), 2.41 (s, 3H), 1.87-1.75(m, 4H), 1.04 (t, 3H, J=7.5 Hz).

IR (KBr tab.) (cm⁻¹): 1699, 1657, 1505, 1428, 1344.

Melting Point (DMF-water): 113°-116° C.

EXAMPLE 18

8-Chloro-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1-methyl-6-nitro-2,4-dioxoquinazoline(Compound 18)

The procedure similar to that described in Example 15 was repeated,except that 510.0 mg (1.24 mmol) of8-chloro-3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-1-methyl-6-nitro-2,4-dioxoquinazoline(Compound d) obtained in Reference Example 10 was used in place ofCompound a, whereby 287.8 mg of crude8-chloro-1,2,3,4-tetrahydro-1-methyl-6-nitro-2,4-dioxo-3-(4-piperidinyl)-quinazolinehydrobromide was obtained. The product (107.2 mg) was treated in thesimilar manner as in Example 15 to give 74.8 mg (yield: 30.3%) ofCompound 18 as pale yellow crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.97 (d, 1H, J=3.0 Hz), 8.69 (s, 1H), 8.53 (d,1H, J=3.0 Hz), 7.32 (s, 1H), 7.16 (s, 1H), 5.12-5.11 (m, 1H), 4.41-4.36(br.-d, 2H), 4.04 (s, 3H), 4.01 (s, 3H), 3.89 (s, 3H), 3.26-3.18 (br.-t,2H), 3.06-2.91 (m, 2H), 1.89-1.86 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1718, 1668, 1607, 1477, 1347.

Melting Point (ethyl acetate-ether): 277°-279° C.

EXAMPLE 19

1-Cyclopropylmethyl-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline(Compound 26)

The procedure similar to that described in Example 1 was repeated,except that 300 mg (0.63 mmol) of Compound 24 was used andcyclopropylmethyl bromide was used in place of methyl iodide. As aresult, 89 mg (yield: 27%) of Compound 26 was obtained as pale yellowcrystals.

¹ H-NMR (CDCl₃) δ(ppm): 9.09 (d, 1H, J=2.5 Hz), 8.64 (s, 1H), 8.53 (dd,1H, J=9.0, 2.5 Hz), 7.44 (d, 1H, J=9.0 Hz), 7.26 (s, 1H), 7.16 (s, 1H),5.35-5.25 (m, 1H), 4.50-4.45 (br.-d, 2H), 4.11 (d, 2H, J=7.0 Hz), 4.08and 4.01 (s for each, 3H), 3.39-3.29 (br.-t, 2H), 3.06-2.91 (m, 2H),1.95-1.89 (br.-d, 2H), 1.24-1.18 (m, 1H), 0.66-0.51 (m, 4H).

IR (KBr tab.) (cm⁻¹): 1713, 1666, 1615, 1511, 1499, 1463, 1336.

Melting Point (ethyl acetate-ether): 193°-195° C.

EXAMPLE 20

6-Chloro-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline(Compound 40)

The procedure similar to that described in Example 1 was repeated,except that 300 mg (0.64 mmol) of6-chloro-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-2,4-dioxoquinazoline(Compound h) obtained according to the method described in theliterature [Chem. Pharm. Bull., 38, 1591-1595 (1990)] was used in placeof Compound 24. As a result, 199.2 mg (yield: 65%) of Compound 40 wasobtained as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.68 (s, 1H), 8.18 (d, 1H, J=1.5 Hz), 7.63 (dd,1H, J=9.0, 1.5 Hz), 7.32 (s, 1H), 7.18 (s, 1H), 7.15 (d, 1H, J=9.0 Hz),5.33-5.21 (m, 1H), 4.40-4.35 (br.-d, 2H), 4.04, 4.01, and 3.59 (s foreach, 3H), 3.25-3.16 (br. -t, 2H), 3.10-3.01 (m, 2H), 1.88-1.87 (br.-d,2H).

IR (KBr tab.) (cm⁻¹): 1700, 1650, 1577, 1463, 1342.

Melting Point (ether): 260°-261° C.

EXAMPLE 21

6-Chloro-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1-ethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline(Compound 41)

The procedure similar to that described in Example 1 was repeated,except that 300 mg (0.64 mmol) of Compound h was used in place ofCompound 24 and ethyl iodide was used in place of methyl iodide. As aresult, 145.9 mg (yield: 45%) of Compound 41 was obtained as whitecrystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.68 (s, 1H), 8.19 (d, 1H, J=1.5 Hz), 7.61 (dd,1H, J=9.0, 1.5 Hz), 7.33 (s, 1H), 7.18 (s, 1H), 7.14 (d, 1H, J=9.0 Hz),5.32-5.21 (m, 1H), 4.41-4.36 (br.-d, 2H), 4.17 (q, 2H, J=7.5 Hz), 4.04and 4.01 (s for each, 3H), 3.24-3.10 (br.-t, 2H), 3.10-2.98 (m, 2H),1.88-1.82 (br.-d, 2H), 1.35 (t, 3H, J=7.5 Hz).

IR (KBr tab.) (cm⁻¹): 1709, 1661, 1575, 1454.

Melting Point (ether): 237°-238° C.

EXAMPLE 22

6-Chloro-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-2,4-dioxo-1-propylquinazoline(Compound 42)

The procedure similar to that described in Example 1 was repeated,except that 300 mg (0.64 mmol) of Compound h was used in place ofCompound 24 and propyl iodide was used in place of methyl iodide. As aresult, 200.9 mg (yield: of Compound 42 was obtained as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.68 (s, 1H), 8.18 (d, 1H, J=1.5 Hz), 7.61 (dd,1H, J=9.0, 1.5 Hz), 7.30 (s, 1H), 7.18 (s, 1H), 7.11 (d, 1H, J=9.0 Hz),5.32-5.21 (m, 1H), 4.39-4.35 (br. -d, 2H), 4.08-3.95 (m, 2H), 4.04 and4.01 (s for each, 3H), 3.24-3.10 (br.-t, 2H), 3.10-2.98 (m, 2H),1.87-1.72 (m, 4H), 1.04 (t, 3H, J=7.4 Hz).

IR (KBr tab.) (cm⁻¹): 1704, 1661, 1578, 1451.

Melting Point (ether): 204°-205° C.

EXAMPLE 23

1-Butyl-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-methyl-2,4-dioxo-quinazoline(Compound 51)

The procedure similar to that described in Example 1 was repeated,except that 300 mg (0.67 mmol) of3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-methyl-2,4-dioxoquinazoline(Compound 22) obtained in Reference Example 4 was used in place ofCompound 24 and butyl iodide was used in place of methyl iodide. As aresult, 253.6 mg (yield: 75%) of Compound 51 was obtained as whitecrystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.67 (s, 1H), 8.02 (d, 1H, J=2.0 Hz), 7.48 (dd,1H, J=8.5, 2.0 Hz), 7.33 (s, 1H), 7.19 (s, 1H), 7.08 (d, 1H, J=8.5 Hz),5.34-5.25 (m, 1H), 4.42-4.37 (br. -d, 2H), 4.08-4.04 (dist.-t, 2H), 4.04and 4.01 (s for each, 3H), 3.26-3.17 (br.-t, 2H), 3.12-3.00 (m, 2H),2.41 (s, 3H), 1.88-1.84 (br.-d, 2H), 1.77-1.66 (m, 2H), 1.00 (t, 3H,J=7.3 Hz).

IR (KBr tab.) (cm⁻¹): 1700, 1656, 1509, 1314, 1211.

Melting Point (ethyl acetate-ether): 185°-186° C.

EXAMPLE 24

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-methyl-2,4-dioxo-1-pentyl-quinazoline(Compound 52)

The procedure similar to that described in Example 1 was repeated,except that 300 mg (0.67 mmol) of Compound 22 was used in place ofCompound 24 and pentyl iodide was used in place of methyl iodide,whereby a free base of Compound 52 was obtained as an oily substance.The product was dissolved in 10 ml of diethyl ether, and 10 ml of asaturated solution of hydrogen chloride in ethyl acetate was addeddropwise to the solution. The precipitated crystals were collected byfiltration, washed with diethyl ether, and dried to give 204.7 mg(yield: 55%) of the hydrochloride of Compound 52 as white crystals.

¹ H-NMR (DMSO-d₆) δ(ppm): 8.82 (s, 1H), 7.85 (s, 1H), 7.59 (d, 1H, J=8.5Hz), 7.37 (s, 2H), 7.36 (d, 1H, J=8.5 Hz), 5.40-5.20 (m, 1H), 4.83-4.77(br.-d, 2H), 4.06-4.04 (m, 2H), 4.00 and 3.96 (s for each, 3H),3.71-3.63 (br.-t, 2H), 2.74-2.70 (m, 2H), 2.36 (S, 3H), 1.93-1.89(br.-d, 2H), 1.65-1.45 (m, 2H), 1.40-1.25 (m, 4H), 0.89 (dist.-t, 3H).

IR (KBr tab.) (cm⁻¹): 1692, 1643, 1511, 1313, 1217.

Melting Point (ether): 240°-243° C.

EXAMPLE 25

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-methyl-2,4-dioxo-1-(2-propenyl)-quinazoline(Compound 53)

The procedure similar to that described in Example 1 was repeated,except that 300 mg (0.67 mmol) of Compound 22 was used in place ofCompound 24 and allyl bromide was used in place of methyl iodide. As aresult, 187.8 mg (yield: 58%) of Compound 53 was obtained as whitecrystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.67 (s, 1H), 8.02 (d, 1H, J=2.0 Hz), 7.45 (dd,1H, J=8.5, 2.0 Hz), 7.31 (s, 1H), 7.19 (s, 1H), 7.06 (d, 1H, J=8.5 Hz),5.97 (ddt, 1H, J=17.0, 10.0, 5.0 Hz), 5.31-5.17 (m, 3H), 4.75 (d, 2H,J=5.0 Hz), 4.39-4.35 (br.-d, 2H), 4.04 and 4.01 (s for each, 3H),3.25-2.99 (m, 4H), 2.41 (s, 3H), 1.89-1.85 (br. -d, 2H).

IR (KBr tab.) (cm⁻¹): 1699, 1656, 1505, 1452, 1335, 1214.

Melting Point (ether): 178°-181° C.

EXAMPLE 26

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,5-dimethyl-2,4-dioxoquinazoline(Compound 57)

The procedure similar to that described in Example 1 was repeated,except that 300 mg (0.67 mmol) of3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-5-methyl-2,4-dioxoquinazoline(Compound 100) obtained in Reference Example 11 was used in place ofCompound 24. As a result, 226.8 mg (yield: 73%) of Compound 57 wasobtained as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.68 (s, 1H), 7.51 (dd, 1H, J=8.0, 7.0 Hz), 7.29and 7.25 (s for each, 1H), 7.07-7.04 (m, 2H), 5.32-5.23 (m, 1H),4.39-4.34 (br. -d, 2H), 4.04, 4.01, and 3.58 (s for each, 3H), 3.23-3.02(m, 4H), 2.81 (s, 3H), 1.88-1.83 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1696, 1654, 1481, 1343, 1212.

Melting Point (ethyl acetate-ether): 230°-231° C.

EXAMPLE 27

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-5-methyl-2,4-dioxo-1-propyl-quinazoline(Compound 58)

The procedure similar to that described in Example 1 was repeated,except that 300 mg (0.67 mmol) of Compound 100 was used in place ofCompound 24 and propyl iodide was used in place of methyl iodide. As aresult, 238.8 mg (yield: 73%) of Compound 58 was obtained as whitecrystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.68 (s, 1H), 7.49 (dd, 1H, J=8.0, 7.0 Hz), 7.26and 7.19 (s for each, 1H), 7.05-7.02 (m, 2H), 5.30-5.21 (m, 1H),4.38-4.33 (br.-d, 2H), 4.06 (dist.-t, 2H), 4.03 and 4.02 (s for each,3H), 3.22-3.03 (m, 4H), 2.82 (s, 3H), 1.87-1.73 (m, 4H), 1.04 (t, 3H,J=7.5 Hz).

IR (KBr tab.) (cm⁻¹): 1675, 1602, 1506, 1452, 1429, 1212.

Melting Point (ethyl acetate-ether): 163°-164° C.

EXAMPLE 28

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,8-dimethyl-2,4-dioxoquinazoline(Compound 59)

The procedure similar to that described in Example 1 was repeated,except that 300 mg (0.67 mmol) of3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-8-methyl-2,4-dioxoquinazoline(Compound 101) obtained in Reference Example 12 was used in place ofCompound 24. As a result, 185.2 mg (yield: 61%) of Compound 59 wasobtained as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.68 (s, 1H), 8.06 (dd, 1H, J=8.0, 1.5 Hz), 7.46(dd, 1H, J=7.0, 1.5 Hz), 7.26 and 7.20 (s for each, 1H), 7.17 (dd, 1H,J=8.0, 7.0 Hz), 5.19-5.12 (m, 1H), 4.36-4.31 (br.-d, 2H), 4.03, 4.01,and 3.67 (s for each, 3H), 3.22-3.01 (m, 4H), 2.61 (s, 3H), 1.89-1.85(br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1697, 1649, 1508, 1462, 1343.

Melting Point (ether): 238°-246° C.

EXAMPLE 29

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1-isobutyl-6-nitro-2,4-dioxo-quinazoline(Compound 25)

The procedure similar to that described in Example 15 was repeated,except that 160.1 mg (0.38 mmol) of3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-1-isobutyl-6-nitro-2,4-dioxoquinazoline(Compound i) was used in place of Compound a, whereby 177.8 mg of crude1,2,3,4-tetrahydro-1-isobutyl-6-nitro-2,4-dioxo-3-(4-piperidinyl)quinazolinehydrobromide was obtained. The product (170.0 mg) was treated in thesimilar manner as in Example 15 to give 69.6 mg (yield: 36%) of Compound25 as pale yellow crystals.

¹ H-NMR (CDCl₃) δ(ppm): 9.09 (d, 1H, J=2.5 Hz), 8.68 (s, 1H), 8.48 (dd,1H, J=9.0, 2.5 Hz), 7.39 (s, 1H), 7.27 (d, 1H, J=9.0 Hz), 7.17 (s, 1H),5.34-5.24 (m, 1H), 4.46-4.42 (br. -d, 2H), 4.05 and 4.01 (s for each,3H), 4.02 (d, 2H, J=8.0 Hz), 3.33-3.21 (br.-t, 2H), 3.07-2.96 (m, 2H),2.21-2.15 (m, 1H), 1.90-1.85 (br.-d, 2H), 1.03 (d, 6H, J=7.0 Hz).

IR (KBr tab.) (cm⁻¹): 1713, 1665, 1613, 1502, 1429, 1332.

Melting Point (ethyl acetate-ether): 146°-147° C.

EXAMPLE 30

1-Cyclohexylmethyl-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-nitro-2,4-dioxo-quinazoline(Compound 27)

The procedure similar to that described in Example 15 was repeated,except that 208.0 mg (0.45 mmol) of1-cyclohexylmethyl-3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline(Compound j) was used in place of Compound a, whereby 269.3 mg of crude1-cyclohexylmethyl-1,2,3,4-tetrahydro-6-nitro-2,4-dioxo-3-(4-piperidinyl)quinazolinehydrobromide was obtained. The product (250 mg) was treated in thesimilar manner as in Example 15 to give 79.9 mg (yield: 34%) of Compound27 as pale yellow crystals

¹ H-NMR (CDCl₃) δ(ppm): 9.09 (d, 1H, J=3.0 Hz), 8.68 (s, 1H), 8.49 (dd,1H, J=9.0, 3.0 Hz), 7.39 (s, 1H), 7.28 (d, 1H, J=9.0 Hz), 7.17 (s, 1H),5.33-5.24 (m, 1H), 4.46-4.41 (br.-d, 2H), 4.05 and 4.02 (s for each,3H), 4.02 (d, 2H, J=7.0 Hz), 3.30-3.20 (br. -t, 2H), 3.07-2.88 (m, 2H),1.89-1.70 (m, 8H), 1.23-1.18 (m, 5H).

IR (KBr tab.) (cm⁻¹): 1667, 1615, 1502, 1330.

Melting Point (ethyl acetate-ether): 135°-136° C.

EXAMPLE 31

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1-(2-dimethylaminoethyl)-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline(Compound 28)

The procedure similar to that described in Example 15 was repeated,except that 460.0 mg (1.10 mmol) of1-(2-dimethylaminoethyl)-3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline(Compound k) was used in place of Compound a, whereby 348.1 mg of crude1-(2-dimethylaminoethyl)-1,2,3,4-tetrahydro-6-nitro-2,4-dioxo-3-(4-piperidinyl)quinazolinehydrobromide was obtained. The product (200 mg) was treated in thesimilar manner as in Example 15 to give 71.7 mg (yield: 21%) of Compound28 as pale yellow crystals.

¹ H-NMR (CDCl₃) δ(ppm): 9.09 (d, 1H, J=2.6 Hz), 8.70 (s, 1H), 8.50 (dd,1H, J=9.5, 2.6 Hz), 7.41 (d, 1H, J=9.5 Hz), 7.27 (s, 1H), 7.18 (s, 1H),5.30-5.15 (m, 1H), 4.40-4.25 (m, 4H), 4.04 and 4.02 (s for each, 3H),3.25-3.15 (br.-t, 2H), 3.15-2.93 (m, 2H), 2.70-2.60 (br. -t, 2H), 2.37(s, 6H), 1.88-1.82 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1714, 1667, 1617, 1504, 1453, 1333.

Melting Point (ethyl acetate-ether): 113°-114° C.

EXAMPLE 32

8-Chloro-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1-ethyl-1,2,3,4-tetrahydro-2,4-dioxo-quinazoline(Compound 35)

The procedure similar to that described in Example 15 was repeated,except that 388.0 mg (1.02 mmol) of8-chloro-3-(1-ethoxycarbonyl-4-piperidinyl)-1-ethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline(Compound l) was used in place of Compound a, whereby 301.8 mg of crude8-chloro-1-ethyl-1,2,3,4-tetrahydro-2,4-dioxo-3-(4-piperidinyl)quinazolinehydrobromide was obtained. The product (300.0 mg) was treated in thesimilar manner as in Example 15 to give 158.6 mg (yield: 32%) ofCompound 35 as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.69 (s, 1H), 8.18 (dd, 1H, J=8.5, 1.5 Hz), 7.69(dd, 1H, J=8.5, 1.5 Hz), 7.27 (s, 1H), 7.18 (s, 1H), 7.18 (dd, 1H,J=8.5, 8.5 Hz), 5.19-5.09 (m, 1H), 4.44 (q, 2H, J=7.0 Hz), 4.37-4.32(br.-d, 2H), 4.04 and 4.02 (s for each, 3H), 3.22-3.13 (br.-t, 2H),3.09-3.00 (m, 2H), 1.89-1.85 (br. -d, 2H), 1.50 (t, 3H, J=7.0 Hz).

IR (KBr tab.) (cm⁻¹): 1709, 1656, 1449, 1335.

Melting Point (ethyl acetate-ether): 211°-212° C.

EXAMPLE 33

8-Chloro-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1-ethyl-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline(Compound 37)

The procedure similar to that described in Example 15 was repeated,except that 300.0 mg (0.71 mmol) of8-chloro-3-(1-ethoxycarbonyl-4-piperidinyl)-1-ethyl-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline(Compound m) was used in place of Compound a, whereby 219.4 mg of crude8-chloro-1-ethyl-1,2,3,4-tetrahydro-6-nitro-2,4-dioxo-3-(4-piperidinyl)quinazolinehydrobromide was obtained. The product (200.0 mg) was treated in thesimilar manner as in Example 15 to give 163.3 mg (yield: 47%) ofCompound 37 as pale yellow crystals.

¹ H-NMR (CDCl₃) δ(ppm): 9.01 (d, 1H, J=2.6 Hz), 8.70 (s, 1H), 8.54 (d,1H, J=2.6 Hz), 7.28 (s, 1H), 7.17 (s, 1H), 5.20-5.08 (m, 1H), 4.51 (q,2H, J=6.6 Hz), 4.37-4.33 (br.-d, 2H), 4.04 and 4.02 (s for each, 3H),3.24-3.15 (br.-t, 2H), 3.06-2.97 (m, 2H), 1.90-1.84 (br.-d, 2H), 1.54(t, 3H, J=6.6 Hz).

IR (KBr tab.) (cm⁻¹): 1718, 1666, 1482, 1430, 1338.

Melting Point (ethyl acetate-ether): 254°-255° C.

EXAMPLE 34

8-Chloro-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-nitro-2,4-dioxo-1-propylquinazoline(Compound 38)

The procedure similar to that described in Example 15 was repeated,except that 300.0 mg (0.68 mmol) of8-chloro-3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-6-nitro-2,4-dioxo-1-propylquinazoline(Compound n) was used in place of Compound a, whereby 119.4 mg of crude8-chloro-1,2,3,4-tetrahydro-6-nitro-2,4-dioxo-3-(4-piperidinyl)-1-propylquinazolinehydrobromide was obtained. The product (110.0 mg) was treated in thesimilar manner as in Example 15 to give 45.1 mg (yield: 13%) of Compound38 as pale yellow crystals.

¹ H-NMR (CDCl₃) δ(ppm): 9.01 (d, 1H, J=2.6 Hz), 8.68 (s, 1H), 8.53 (d,1H, J=2.6 Hz), 7.35 (s, 1H), 7.17 (s, 1H), 5.20-5.10 (m, 1H), 4.44-4.38(m, 4H), 4.05 and 4.02 (s for each, 3H), 3.30-3.15 (br. -t, 2H),3.08-2.90 (m, 2H), 1.89-1.71 (m, 4H), 0.98 (t, 3H, J=7.5 Hz).

IR (KBr tab.) (cm⁻¹): 1669, 1606, 1453, 1338.

Melting Point (ethyl acetate-ether): 209°-210° C.

EXAMPLE 35

6-Chloro-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1-ethyl-1,2,3,4-tetrahydro-8-nitro-2,4-dioxoquinazoline(Compound 43)

The procedure similar to that described in Example 15 was repeated,except that 600.0 mg (1.53 mmol) of6-chloro-3-(1-ethoxycarbonyl-4-piperidinyl)-1-ethyl-1,2,3,4-tetrahydro-8-nitro-2,4-dioxoquinazoline(Compound o) was used in place of Compound a, whereby 480.3 mg of crude6-chloro-1-ethyl-1,2,3,4-tetrahydro-8-nitro-2,4-dioxo-3-(4-piperidinyl)-quinazolinehydrobromide was obtained. The product (480.0 mg) was treated in thesimilar manner as in Example 15 to give 396.8 mg (yield: 48%) ofCompound 43 as pale yellow crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.69 (s, 1H), 8.38 (d, 1H, J=2.5 Hz), 7.86 (d,1H, J=2.5 Hz), 7.31 (s, 1H), 7.17 (s, 1H), 5.18-5.12 (m, 1H), 4.40-4.36(br. -d, 2H), 4.04 and 4.01 (s for each, 3H), 3.88 (q, 2H, J=7.0 Hz),3.25-3.16 (br.-t, 2H), 3.06-2.91 (m, 2H), 1.91-1.87 (br. -d, 2H), 1.28(t, 3H, J=7.0 Hz).

IR (KBr tab.) (cm⁻¹): 1713, 1666, 1575, 1504, 1476, 1431, 1343.

Melting Point (ether): 254°-256° C.

EXAMPLE 36

6-Chloro-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-8-nitro-2,4-dioxo-1-propylquinazoline(Compound 44)

The procedure similar to that described in Example 15 was repeated,except that 600.0 mg (1.41 mmol) of6-chloro-3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-8-nitro-2,4-dioxo-1-propylquinazoline(Compound p) was used in place of Compound a, whereby 415.1 mg of crude6-chloro-1,2,3,4-tetrahydro-8-nitro-2,4-dioxo-3-(4-piperidinyl)-1-propylquinazolinehydrobromide was obtained. The product (410.0 mg) was treated in thesimilar manner as in Example 15 to give 174.5 mg (yield: 23%) ofCompound 44 as pale yellow crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.69 (s, 1H), 8.38 (d, 1H, J=2.5 Hz), 7.86 (d,1H, J=2.5 Hz), 7.35 (s, 1H), 7.16 (s, 1H), 5.20-5.10 (m, 1H), 4.42-4.38(br. -d, 2H), 4.05 and 4.01 (s for each, 3H), 3.85-3.79 (dist.-t, 2H),3.26-3.17 (br.-t, 2H), 3.06-2.92 (m, 2H), 1.91-1.87 (br. -d, 2H),1.70-1.56 (m, 2H), 0.83 (t, 3H, J=7.3 Hz).

IR (KBr tab.) (cm⁻¹): 1714, 1671, 1476, 1431, 1342.

Melting Point (ethyl acetate-ether): 255°-257° C.

EXAMPLE 37

6-Bromo-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1-methyl-2,4-dioxo-quinazoline(Compound 45)

The procedure similar to that described in Example 15 was repeated,except that 397.3 mg (0.97 mmol) of6-bromo-3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline(Compound q) was used in place of Compound a, whereby 210.0 mg of crude6-bromo-1,2,3,4-tetrahydro-1-methyl-2,4-dioxo-3-(4-piperidinyl)quinazoline hydrobromide was obtained. The product (203.5 mg) wastreated in the similar manner as in Example 15 to give 48.6 mg (yield:10%) of Compound 45 as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.68 (s, 1H), 8.33 (d, 1H, J=2.0 Hz), 7.76 (dd,1H, J=9.0, 2.0 Hz), 7.31 (s, 1H), 7.18 (s, 1H), 7.07 (d, 1H, J=9.0 Hz),5.31-5.23 (m, 1H), 4.40-4.35 (br.-d, 2H), 4.04, 4.01, and 3.58 (s foreach, 3H), 3.25-3.16 (br. -t, 2H), 3.10-2.96 (m, 2H), 1.88-1.84 (br.-d,2H).

IR (KBr tab.) (cm⁻¹): 1698, 1655, 1465, 1343.

Melting Point (ether): 258°-260° C.

EXAMPLE 38

6-Bromo-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1-ethyl-1,2,3,4-tetrahydro-2,4-dioxo-quinazoline (Compound 46)

The procedure similar to that described in Example 15 was repeated,except that 300.0 mg (0.71 mmol) of6-bromo-3-(1-ethoxycarbonyl-4-piperidinyl)-1-ethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline(Compound r) was used in place of Compound a, whereby 131.9 mg of crude6-bromo-1-ethyl-1,2,3,4-tetrahydro-2,4-dioxo-3-(4-piperidinyl)quinazoline hydrobromide was obtained. The product (130.0 mg) wastreated in the similar manner as in Example 15 to give 75.1 mg (yield:20%) of Compound 46 as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.68 (s, 1H), 8.34 (d, 1H, J=2.5 Hz), 7.75 (dd,1H, J=8.9, 2.5 Hz), 7.34 (s, 1H), 7.18 (s, 1H), 7.09 (d, 1H, J=8.9 Hz),5.31-5.24 (m, 1H), 4.42-4.38 (br.-d, 2H), 4.16 (q, 2H, J=7.0 Hz), 4.04and 4.01 (s for each, 3H), 3.26-3.17 (br.-t, 2H), 3.06-3.01 (m, 2H),1.88-1.83 (br.-d, 2H), 1.35 (t, 3H, J=7.0 Hz).

IR (KBr tab.) (cm⁻¹): 1704, 1659, 1505, 1484, 1451, 1429, 1339.

Melting Point (ethyl acetate-ether): 249°-250° C.

EXAMPLE 39

6,8-Dibromo-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1-ethyl-1,2,3,4-tetrahydro-2,4-dioxo-quinazoline(Compound 48)

The procedure similar to that described in Example 15 was repeated,except that 180.0 mg (0.43 mmol) of6,8-dibromo-3-(1-ethoxycarbonyl-4-piperidinyl)-1-ethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline(Compound s) was used in place of Compound a, whereby 112.3 mg of crude6,8-dibromo-1-ethyl-1,2,3,4-tetrahydro-2,4-dioxo-3-(4-piperidinyl)quinazoline hydrobromide was obtained. The product (95.3 mg) was treatedin the similar manner as in Example 15 to give 37.5 mg (yield: 16%) ofCompound 48 as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.69 (s, 1H), 8.31 (d, 1H, J=2.5 Hz), 8.03 (d,1H, J=2.5 Hz), 7.33 (s, 1H), 7.17 (s, 1H), 5.09-5.05 (m, 1H), 4.45 (q,2H, J=7.0 Hz), 4.44-4.36 (br. -d, 2H), 4.04 and 4.01 (s for each, 3H),3.24-3.15 (br. -t, 2H), 3.04-2.92 (m, 2H), 1.90-1.85 (br.-d, 2H), 1.47(t, 3H, J=7.0 Hz).

IR (KBr tab.) (cm⁻¹): 1708, 1667, 1504, 1451, 1428, 1332.

Melting Point (ether): 229°-230° C.

EXAMPLE 40

7-Chloro-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1-ethyl-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline(Compound 36)

The procedure similar to that described in Example 15 was repeated,except that 200.0 mg (0.47 mmol) of7-chloro-3-(1-ethoxycarbonyl-4-piperidinyl)-1-ethyl-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline(Compound t) was used in place of Compound a, whereby 150.6 mg of crude7-chloro-1-ethyl-1,2,3,4-tetrahydro-6-nitro-2,4-dioxo-3-(4-piperidinyl)-quinazolinehydrobromide was obtained. The product (145.0 mg, 0.31 mmol) wassuspended in 10 ml of methanol, and 70 mg (0.31 mmol) of4-chloro-6,7-dimethoxyquinazoline and 0.11 ml (0.78 mmol) oftriethylamine were added thereto, followed by heating under reflux for 1hour. After the reaction mixture was cooled to room temperature, waterwas added, and the precipitated crystals were collected by filtration,washed successively with water, methanol, and ether, and dried.Recrystallization of the resulting crude crystals from methanol/watergave 144.6 mg (yield from Compound t: 60%) of Compound 36 as pale yellowcrystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.83 (s, 1H), 8.69 (s, 1H), 7.32 (s, 1H), 7.31(s, 1H), 7.17 (s, 1H), 5.28-5.19 (m, 1H), 4.40-4.35 (br.-d, 2H), 4.19(q, 1H, J=7.4 Hz), 4.04 and 4.01 (s for each, 3H), 3.26-3.17 (br.-t,2H), 3.07-2.97 (m, 2H), 1.88-1.84 (br.-d, 2H), 1.40 (t, 3H, J=7.4 Hz).

IR (KBr tab.) (cm⁻¹): 1715, 1662, 1610, 1502, 1449, 1335.

Melting Point (methanol-water); 216°-217° C.

EXAMPLE 41

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline(Compound 50)

The procedure similar to that described in Example 15 was repeated,except that 6.2 g (18.0 mmol) of3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline(Compound u) was used in place of Compound a, whereby 6.1 g of crude1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)quinazolinehydrobromide (Compound v) was obtained. The product (2.0 g) was treatedin the similar manner as in Example 40 to give 2.46 g of crude Compound50 as white crystals. The crystals were suspended in 100 ml of methanol,and a saturated solution of hydrogen chloride in ethyl acetate was addedthereto in excess, followed by stirring at room temperature for 10minutes. The precipitated crystals were collected by filtration andrecrystallized from methanol/water to give 2.2 g (yield from Compound u:69%) of the hydrochloride of Compound 50 as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.60 (s, 1H), 8.00 (d, 1H, J=1.5 Hz), 7.72 (s,1H), 7.50 (dd, 1H, J=8.4, 1.5 Hz), 7.17 (s, 1H), 7.10 (d, 1H, J=8.4 Hz),5.43-5.34 (m, 1H), 4.73-4.68 (br.-d, 2H), 4.09, 4.00, and 3.58 (s foreach, 3H), 3.44-3.35 (br.-t, 2H), 3.05-2.99 (m, 2H), 2.42 (s, 3H),1.95-1.92 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1695, 1649, 1508, 1474, 1362.

Melting Point (methanol-water): 218°-220° C.

EXAMPLE 42

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1-isopropyl-6-nitro-2,4-dioxoquinazoline(Compound 31)

The procedure similar to that described in Example 15 was repeated,except that 100.0 mg (0.25 mmol) of3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-1-isopropyl-6-nitro-2,4-dioxoquinazoline(Compound w) was used in place of Compound a, whereby 103.5 mg of crude1,2,3,4-tetrahydro-1-isopropyl-6-nitro-2,4-dioxo-3-(4-piperidinyl)quinazoline hydrobromide was obtained. The product was treated in thesimilar manner as in Example 40 to give 44.4 mg (yield: 36%) of Compound31 as pale yellow crystals.

¹ H-NMR (CDCl₃) δ(ppm): 9.08 (d, 1H, J=2.5 Hz), 8.68 (s, 1H), 8.48 (dd,1H, J=8.5, 2.5 Hz), 7.47 (d, 1H, J=8.5 Hz), 7.37 (s, 1H), 7.18 (s, 1H),5.30-5.15 (m, 1H), 5.10-4.95 (m, 1H), 4.45-4.40 (br.-d, 2H), 4.05 and4.02 (s for each, 3H), 3.28-3.20 (br.-t, 2H), 3.08-2.95 (m, 2H),1.90-1.86 (br.-d, 2H), 1.65 (d, 6H, J=7.0 Hz).

IR (KBr tab.) (cm⁻¹): 1713, 1667, 1612, 1494, 1321.

Melting Point (ethyl acetate-ether): 216°-217° C.

EXAMPLE 43

1-(sec-Butyl)-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-nitro-2,4-dioxo-quinazoline(Compound 32)

The procedure similar to that described in Example 42 was repeated,except that 107.0 mg (0.25 mmol) of1-(sec-butyl)-3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline(Compound x) was used in place of Compound a, whereby 71.2 mg (yield:53%) of Compound 32 was obtained as pale yellow crystals.

¹ H-NMR (CDCl₃) δ(ppm): 9.09 (d, 1H, J=2.5 Hz), 8.68 (s, 1H), 8.45 (dd,1H, J=9.5, 2.5 Hz), 7.47 (d, 1H, J=9.5 Hz), 7.36 (s, 1H), 7.18 (s, 1H),5.30-5.15 (m, 1H), 5.00-4.60 (m, 1H), 4.44-4.39 (br.-d, 2H), 4.04 and4.02 (s for each, 3H), 3.28-3.19 (br.-t, 2H), 3.07-2.95 (m, 2H),2.30-2.00 (m, 2H), 1.89-1.85 (br.-d, 2H), 1.62 (d, 3H, J=6.5 Hz), 0.92(t, 3H, J=7.5 Hz).

IR (KBr tab.) (cm⁻¹): 1716, 1671, 1614, 1454, 1330, 208.

Melting Point (ethyl acetate-ether): 156°-158° C.

EXAMPLE 44

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1-ethyl-1,2,3,4-tetrahydro-6,8-dinitro-2,4-dioxoquinazoline (Compound 39)

The procedure similar to that described in Example 15 was repeated,except that 360.0 mg (0.89 mmol) of3-(1-ethoxycarbonyl-4-piperidinyl)-1-ethyl-1,2,3,4-tetrahydro-6,8-dinitro-2,4-dioxoquinazoline(Compound y) was used in place of Compound a, whereby 429.3 mg of crude1-ethyl-1,2,3,4-tetrahydro-6,8-dinitro-2,4-dioxo-3-(4-piperidinyl)quinazolinehydrobromide was obtained. The product (200.0 mg) was treated in thesimilar manner as in Example 40 to give 71.0 mg (yield: 31%) of Compound39 as pale yellow crystals.

¹ H-NMR (CDCl₃) δ(ppm): 9.23 (d, 1H, J=2.5 Hz), 8.72 (d, 1H, J=2.5 Hz),8.69 (s, 1H), 7.40 (s, 1H), 7.16 (s, 1H), 5.23-5.14 (m, 1H), 4.47-4.42(br. -d, 2H), 4.06 and 4.02 (s for each, 3H), 3.96 (q, 2H, J=7.3 Hz),3.31-3.22 (br.-t, 2H), 3.03-2.91 (m, 2H), 1.93-1.90 (br.-d, 2H), 1.33(d, 3H, J=7.3 Hz).

IR (KBr tab.) (cm⁻¹): 1674, 1612, 1341.

Melting Point (ethyl acetate-ether): 223°-224° C.

EXAMPLE 45

6-Bromo-7-chloro-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1-ethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline(Compound 47)

The procedure similar to that described in Example 15 was repeated,except that 200.0 mg (0.44 mmol) of6-bromo-7-chloro-3-(1-ethoxycarbonyl-4-piperidinyl)-1-ethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline(Compound z) was used in place of Compound a, whereby 90.4 mg of crude6-bromo-7-chloro-1-ethyl-1,2,3,4-tetrahydro-2,4-dioxo-3-(4-piperidinyl)quinazolinehydrobromide was obtained. The product (85.0 mg) was treated in thesimilar manner as in Example 40 to give 69.0 mg (yield: 30%) of Compound47 as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.83 (s, 1H), 8.69 (s, 1H), 7.32 (s, 1H), 7.31(s, 1H), 7.17 (s, 1H), 5.28-5.19 (m, 1H), 4.40-4.35 (br.-d, 2H), 4.19(q, 2H, J=7.4 Hz), 4.04 and 4.01 (s for each, 3H), 3.26-3.17 (br.-t,2H), 3.07-2.97 (m, 2H), 1.88-1.84 (br.-d, 2H), 1.40 (t, 3H, J=7.4 Hz).

IR (KBr tab.) (cm⁻¹): 1715, 1662, 1610, 1502, 1449, 1335.

Melting Point (methanol-water): 216°-217° C.

EXAMPLE 46

7-Chloro-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1-ethyl-1,2,3,4-tetrahydro-2,4-dioxo-quinazoline(Compound 49)

The procedure similar to that described in Example 15 was repeated,except that 200.0 mg (0.53 mmol) of7-chloro-3-(1-ethoxycarbonyl-4-piperidinyl)-1-ethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline(Compound aa) was used in place of Compound a, whereby 178.3 mg of crude7-chloro-1-ethyl-1,2,3,4-tetrahydro-2,4-dioxo-3-(4-piperidinyl)quinazolinehydrobromide was obtained. The product (170.0 mg) was treated in thesimilar manner as in Example 40 to give 134.2 mg (yield: 57%) ofCompound 49 as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.65 (s, 1H), 8.15 (d, 1H, J=8.5 Hz), 7.25-7.17(m, 4H), 5.35-5.18 (m, 1H), 4.50-4.35 (br.-d, 2H), 4.13 (q, 2H, J=7.0Hz), 4.06 and 4.00 (s for each, 3H), 3.27-3.23 (br.-t, 2H), 3.03-2.99(m, 2H), 1.95-1.86 (br.-d, 2H), 1.37 (t, 3H, J=7.0 Hz).

IR (KBr tab.) (cm⁻¹): 1712, 1663, 1606, 1465.

Melting Point (isopropyl alcohol): 183°-184° C.

EXAMPLE 47

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-6-ethyl-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline(Compound 54)

The procedure similar to that described in Example 15 was repeated,except that 250.0 mg (0.73 mmol) of3-(1-ethoxycarbonyl-4-piperidinyl)-6-ethyl-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline(Compound bb) was used in place of Compound a, whereby 270.0 mg of crude6-ethyl-1,2,3,4-tetrahydro-1-methyl-2,4-dioxo-3-(4-piperidinyl)quinazoline hydrobromide was obtained. The product (260.0 mg) wastreated in the similar manner as in Example 40 to give 256.3 mg (yield:76%) of Compound 54 as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.69 (s, 1H), 8.04 (d, 1H, J=1.5 Hz), 7.52 (dd,1H, J=8.5, 1.5 Hz), 7.26 (s, 1H), 7.19 (s, 1H), 7.12 (d, 1H, J=8.5 Hz),5.35-5.15 (m, 1H), 4.35-4.30 (br.-d, 2H), 4.03, 4.01, and 3.59 (s foreach, 3H), 3.18-3.05 (m, 4H), 2.72 (q, 2H, J=7.0 Hz), 1.87-1.79 (br.-d,2H), 1.27 (t, 3H, J=7.0 Hz).

IR (KBr tab.) (cm⁻¹): 1700, 1652, 1512, 1506, 1331, 1213.

Melting Point (ethyl acetate): 202°-203° C.

EXAMPLE 48

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1-methyl-2,4-dioxo-6-propyl-quinazoline(Compound 55)

The procedure similar to that described in Example 15 was repeated,except that 84.0 mg (0.23 mmol) of3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-1-methyl-2,4-dioxo-6-propylquinazoline(Compound cc) was used in place of Compound a, whereby 103.0 mg of crude1,2,3,4-tetrahydro-1-methyl-2,4-dioxo-3-(4-piperidinyl)-6-propylquinazolinehydrobromide was obtained. The product was treated in the similar manneras in Example 40 to give 42.1 mg (yield: 37%) of Compound 55 as whitecrystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.67 (s, 1H), 8.02 (d, 1H, J=2.0 Hz), 7.50 (dd,1H, J=8.5, 2.0 Hz), 7.35 (s, 1H), 7.19 (s, 1H), 7.12 (d, 1H, J=8.5 Hz),5.36-5.27 (m, 1H), 4.43-4.38 (br.-d, 2H), 4.04, 4.01, and 3.58 (s foreach, 3H), 3.28-3.18 (br.-t, 2H), 3.12-3.00 (m, 2H), 2.67 (t, 2H, J=7.5Hz), 1.89-1.85 (br.-d, 2H), 1.67 (sext, 2H, J=7.5 Hz), 0.94 (t, 3H,J=7.5 Hz).

IR (KBr tab.) (cm⁻¹): 1696, 1651, 1501, 1338.

Melting Point (ether): 130°-133° C.

EXAMPLE 49

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-isopropyl-1-methyl-2,4-dioxoquinazoline(Compound 56)

The procedure similar to that described in Example 15 was repeated,except that 150.0 mg (0.40 mmol) of3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-6-isopropyl-6-methyl-2,4-dioxoquinazoline (Compound dd) wasused in place of Compound a, whereby 155.1 mg of crude 1, 2,3,4-tetrahydro-6-isopropyl-1-methyl-2,4-dioxo-3-(4-piperidinyl)quinazolinehydrobromide was obtained. The product (150.0 mg) was treated in thesimilar manner as in Example 40 to give 118.1 mg (yield: 62%) ofCompound 56 as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.68 (s, 1H), 8.07 (d, 1H, J=1.5 Hz), 7.55 (dd,1H, J=8.5, 1.5 Hz), 7.24 (s, 1H), 7.19 (s, 1H), 7.12 (d, 1H, J=8.5 Hz),5.32-5.24 (m, 1H), 4.33-4.29 (br.-d, 2H), 4.02, 4.00, and 3.58 (s foreach, 3H), 3.22-2.94 (m, 5H), 1.86-1.81 (br.-d, 2H), 1.28 (d, 6H, J=7.0Hz).

IR (KBr tab.) (cm⁻¹): 1701, 1657, 1510, 1475, 1426, 1334, 1212.

Melting Point (ethyl acetate-ether): 195°-196° C.

EXAMPLE 50

6-Acetyl-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline(Compound 63)

The procedure similar to that described in Example 15 was repeated,except that 200.0 mg (0.54 mmol) of6-acetyl-3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline (Compound ee) was used inplace of Compound a, whereby 146.2 mg of crude6-acetyl-1,2,3,4-tetrahydro-1-methyl-2,4-dioxo-3-(4-piperidinyl)quinazolinehydrobromide was obtained. The product (140.0 mg) was treated in thesimilar manner as in Example 40 to give 163.7 mg (yield: 64%) ofCompound 63 as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.76 (d, 1H, J=2.0 Hz), 8.69 (s, 1H), 8.32 (dd,1H, J=8.5, 2.0 Hz), 7.34 (s, 1H), 7.28 (d, 1H, J=8.5 Hz), 7.18 (s, 1H),5.35-5.26 (m, 1H), 4.43-4.38 (br.-d, 2H), 4.06, 4.02, and 3.65 (s foreach, 3H), 3.28-3.19 (br.-t, 2H), 3.10-2.98 (m, 2H), 2.67 (s, 3H),1.90-1.86 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1700, 1665, 1610, 1500, 1460, 1340, 1235, 831.

Melting Point (methanol-water): 216°-218° C.

EXAMPLE 51

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1-ethyl-1,2,3,4-tetrahydro-6-hydroxy-2,4-dioxoquinazoline(Compound 66)

The procedure similar to that described in Example 15 was repeated,except that 490.0 mg (1.31 mmol) of3-(1-ethoxycarbonyl-4-piperidinyl)-1-ethyl-1,2,3,4-tetrahydro-6-methoxy-2,4-dioxoquinazoline(Compound ff) was used in place of Compound a, whereby 284.1 mg of crude1-ethyl-1,2,3,4-tetrahydro-6-hydroxy-2,4-dioxo-3-(4-piperidinyl)quinazolinehydrobromide was obtained. The product (270.0 mg) was treated in thesimilar manner as in Example 40 to give 203.5 mg (yield: 34%) ofCompound 66 as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.67 (s, 1H), 7.78 (d, 1H, J=3.0 Hz), 7.30-7.27(m, 2H), 7.18 (s, 1H), 7.09 (d, 1H, J=8.5 Hz), 5.27-5.23 (m, 1H),4.46-4.42 (br.-d, 2H), 4.16 (dist.-q, 2H), 3.99 (s, 6H), 3.29-3.20(br.-t, 2H), 3.10-2.98 (m, 2H), 1.86-1.82 (br.-d, 2H), 1.35 (dist. -t,3H).

IR (KBr tab.) (cm⁻¹): 1694, 1648, 1505, 1476.

Melting Point (ether): 290°-291° C. (decomposition)

EXAMPLE 52

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-hydroxy-2,4-dioxo-1-propyl-quinazoline(Compound 67)

The procedure similar to that described in Example 15 was repeated,except that 265.0 mg (0.68 mmol) of3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-6-methoxy-2,4-dioxo-1-propylquinazoline (Compound gg) wasused in place of Compound a, whereby 216.1 mg of crude1,2,3,4-tetrahydro-6-hydroxy-2,4-dioxo-3-(4-piperidinyl)-1-propylquinazolinehydrobromide was obtained. The product (200.0 mg) was treated in thesimilar manner as in Example 40 to give 170.5 mg (yield: 55%) ofCompound 67 as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.66 (s, 1H), 7.77 (d, 1H, J=3.0 Hz), 7.28-7.25(m, 2H), 7.17 (s, 1H), 7.07 (d, 1H, J=8.9 Hz), 5.32-5.23 (m, 1H),4.46-4.42 (br.-d, 2H), 4.04 (dist.-t, 2H), 4.00 (s, 6H), 3.29-3.21(br.-t, 2H), 3.07-3.01 (m, 2H), 1.86-1.73 (m, 4H), 1.04 (t, 3H, J=7.5Hz).

IR (KBr tab.) (cm⁻¹): 1695, 1646, 1504, 1480, 1343.

Melting Point (ether): 263°-264° C.

EXAMPLE 53

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-7-methoxy-1-methyl-2,4-dioxo-quinazoline(Compound 74)

The procedure similar to that described in Example 15 was repeated,except that 750.0 mg (2.08 mmol) of3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-7-methoxy-1-methyl-2,4-dioxoquinazoline(Compound hh) was used in place of Compound a, whereby crude1,2,3,4-tetrahydro-7-methoxy-1-methyl-2,4-dioxo-3-(4-piperidinyl)quinazoline hydrobromide was obtained. The product was treated in thesimilar manner as in Example 40 to give 193.5 mg (yield: 20%) ofCompound 74 as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.69 (s, 1H), 8.15 (d, 1H, J=9.0 Hz), 7.25 (s,1H), 7.19 (s, 1H), 6.80 (dd, 1H, J=9.0, 2.0 Hz), 6.60 (d, 1H, J=2.0 Hz),5.33-5.23 (m, 1H), 4.34-4.30 (br.-d, 2H), 4.03, 4.01, 3.93, and 3.57 (sfor each, 3H), 3.17-3.03 (m, 4H), 1.87-1.82 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1695, 1655, 1620, 1502, 1422, 365, 1338, 1230.

Melting Point (ethyl acetate-ether): 214°-216° C.

EXAMPLE 54

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-7-hydroxy-1-methyl-2,4-dioxo-quinazoline(Compound 68)

The procedure similar to that described in Example 15 was repeated,except that 320.0 mg (0.89 mmol) of Compound hh was used in place ofCompound a and the reaction was carried out for 3 hours, whereby amixture of1,2,3,4-tetrahydro-7-methoxy-1-methyl-2,4-dioxo-3-(4-piperidinyl)-quinazolinehydrobromide and1,2,3,4-tetrahydro-7-hydroxy-1-methyl-2,4-dioxo-3-(4-piperidinyl)quinazoline hydrobromide at a ratio of about 1:1 was obtained. Thiscrude product was treated in the similar manner as in Example 40 to givea mixture of Compound 74 and Compound 68. The obtained mixture waspurified by silica gel column chromatography (eluent:chloroform/methanol=100/1) to give 55.6 mg (yield: 13%) of whitecrystals of Compound 68 as a second eluted component.

¹ H-NMR (CDCl₃) δ(ppm): 8.66 (s, 1H), 8.07 (d, 1H, J=9.0 Hz), 7.23 (s,1H), 7.18 (s, 1H), 6.77 (dd, 1H, J=9.0, 2.0 Hz), 6.65 (d, 1H, J=2.0 Hz),5.35-5.26 (m, 1H), 4.47-4.42 (br.-d, 2H), 4.00, 3.99, and 3.51 (s foreach, 3H), 3.30-3.21 (br.-t, 2H), 3.08-2.96 (m, 2H), 1.85-1.81 (br.-d,2H).

IR (KBr tab.) (cm⁻¹): 1694, 1653, 1622, 1503, 1426, 1342.

Melting Point (ethyl acetate-ether): 226°-270° C.

EXAMPLE 55

3-[1-(2-Chloro-6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1-ethyl-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline(Compound 79)

The procedure similar to that described in Example 15 was repeated,except that 3.62 g (9.4 mmol) of3-(1-ethoxycarbonyl-4-piperidinyl)-1-ethyl-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline(Compound ii) was used in place of Compound a, whereby 3.20 g of crude1-ethyl-1,2,3,4-tetrahydro-6-nitro-2,4-dioxo-3-(4-piperidinyl)quinazolinehydrobromide (Compound jj) was obtained. The product (198.0 mg) wastreated in the similar manner as in Example 40, except for the use of2,4-dichloro-6,7-dimethoxy-quinazoline in place of4-chloro-6,7-dimethoxy-quinazoline, to give 220.7 mg (yield: 78%) ofCompound 79 as pale yellow crystals.

¹ H-NMR (CDCl₃) δ(ppm): 9.09 (d, 1H, J=3.0 Hz), 8.50 (dd, 1H, J=9.0, 3.0Hz), 7.32 (d, 1H, J=9.0 Hz), 7.24 (s, 1H), 7.13 (s, 1H), 5.33-5.22 (m,1H), 4.49-4.44 (br.-d, 2H), 4.24 (q, 2H, J=7.0 Hz), 4.01 and 4.00 (s foreach, 3H), 3.30-3.21 (br.-t, 2H), 3.03-2.98 (m, 2H) 1.90-1.87 (br.-d,2H), 1.40 (t, 3H, J=7.0 Hz).

IR (KBr tab.) (cm⁻¹): 1715, 1664, 1617, 1501, 1340.

Melting Point (ether) 295°-296° C.

EXAMPLE 56

3-[1-(6,7-Dimethoxy-2-methyl-4-quinazolinyl)-4-piperidinyl]-1-ethyl-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline(Compound 81)

The procedure similar to that described in Example 40 was repeated,except that 198.0 mg of crude1-ethyl-1,2,3,4-tetrahydro-6-nitro-2,4-dioxo-3-(4-piperidinyl)quinazolinehydrobromide (Compound jj) obtained in Example 55 was used and4-chloro-6,7-dimethoxy-2-methylquinazoline was used in place of4-chloro-6,7-dimethoxyquinazoline. As a result, 114.0 mg (yield fromCompound ii: 44%) of Compound 81 was obtained as pale yellow crystals.

¹ H-NMR (CDCl₃) δ(ppm): 9.08 (d, 1H, J=2.5 Hz), 8.50 (dd, 1H, J=9.0, 2.5Hz), 7.31 (d, 1H, J=9.0 Hz), 7.25 (s, 1H), 7.14 (s, 1H), 5.26-5.21 (m,1H), 4.45-4.40 (br.-d, 2H), 4.23 (q, 2H, J=7.0 Hz), 4.02 and 3.98 (s foreach, 3H), 3.26-3.16 (br.-t, 2H), 3.06-2.98 (m, 2H), 2.70 (s, 3H),1.89-1.84 (br.-d, 2H), 1.39 (t, 3H, J=7.0 Hz).

IR (KBr tab.) (cm⁻¹): 1715, 1663, 1616, 1502, 1328.

Melting Point (ether): 246°-247° C.

EXAMPLE 57

3-[1-(6,7-Dimethoxy-1,2,3-benzotriazin-4-yl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-quinazoline (Compound 75)

The procedure similar to that described in Example 40 was repeated,except that 354.0 mg (1.0 mmol) of1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)-quinazolinehydrobromide (Compound v) obtained in Example 41 was used,4-methanesulfonyl-6,7-dimethoxy-1,2,3-benzotriazine was used in place of4-chloro-6,7-dimethoxyquinazoline, DMSO was used as a reaction solventin place of methanol, and the reaction was conducted at roomtemperature. As a result, 307.6 mg (yield: 67%) of Compound 75 wasobtained as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 7.98 (d, 1H, J=1.5 Hz), 7.55 (s, 1H), 7.56 (dd,1H, J=7.5, 1.5 Hz), 7.14 (d, 1H, J=7.5 Hz), 7.13 (s, 1H), 5.40-5.25 (m,1H), 4.51-4.47 (br.-d, 2H), 4.10, 4.07, and 3.58 (s for each, 3H),3.36-3.27 (br.-t, 2H), 3.09-3.05 (m, 2H), 2.43 (s, 3H), 1.91-1.87(br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1700, 1656, 1497, 1466, 1428, 1291.

Melting Point (DMF-water): 236°-237° C. (decomposition)

EXAMPLE 58

3-[1-(4-Chloro-6,7-dimethoxy-1-phthalazinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-quinazoline(Compound 76)

The procedure similar to that described in Example 15 was repeated,except that 354.0 mg (1.0 mmol) of1,2,3,4tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)-quinazolinehydrobromide (Compound v) obtained in Example 41 was used,1,4-dichloro-6,7-dimethoxyphthalazine was used in place of4-chloro-6,7-dimethoxyquinazoline, and a catalytic amount of potassiumiodide was added. As a result, 243.7 mg (yield: 49%) of Compound 76 wasobtained as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.02 (d, 1H, J=1.5 Hz), 7.49 (dd, 1H, J=8.5, 1.5Hz), 7.43 (s, 1H), 7.39 (s, 1H), 7.09 (d, 1H, J=8.5 Hz), 5.30-5.25 (m,1H), 4.09 (s, 6H), 3.94-3.90 (br.-d, 2H), 3.59 (s, 3H), 3.24-3.09 (m,4H), 2.43 (s, 3H), 1.88-1.85 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1702, 1653, 1649, 1510, 1421, 315, 1211.

Melting Point (ethyl acetate-ether): 202°-205° C.

EXAMPLE 59

3-[1-(2-Chloro-6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-quinazoline(Compound 78)

The procedure similar to that described in Example 40 was repeated,except that 354.0 mg (1.0 mmol) of1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)-quinazolinehydrobromide (Compound v) obtained in Example 41 was used and2,4-dichloro-6,7-dimethoxyquinazoline was used in place of4-chloro-6,7-dimethoxyquinazoline. As a result, 239.2 mg (yield: 48%) ofCompound 78 was obtained as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.01 (d, 1H, J=l.0 Hz), 7.55 (dd, 1H, J=8.5, 1.0Hz), 7.26 (s, 1H), 7.14 (s, 1H), 7.10 (d, 1H, J=8.5 Hz), 5.38-5.26 (m,1H), 4.50-4.45 (br.-d, 2H), 4.01, 3.99, and 3.58 (s for each, 3H),3.29-3.20 (br.-t, 2H), 3.11-2.96 (m, 2H), 2.42 (s, 3H), 1.90-1.85(br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1706, 1655, 1512, 1480, 1218.

Melting Point (ether): 234°-236° C.

EXAMPLE 60

3-[1-(6,7-Dimethoxy-2-methyl-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline(Compound 80)

The procedure similar to that described in Example 40 was repeated,except that 354.0 mg (1.0 mmol) of1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)-quinazolinehydrobromide (Compound v) obtained in Example 41 was used and4-chloro-6,7-dimethoxy-2-methylquinazoline was used in place of4-chloro-6,7-dimethoxyquinazoline. As a result, 53.1 mg (yield: 10%) ofCompound 80 was obtained as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.01 (d, 1H, J=2.0 Hz), 7.49 (dd, 1H, J=8.5, 2.0Hz), 7.26 (s, 1H), 7.17 (s, 1H), 7.09 (d, 1H, J=8.5 Hz), 5.32-5.24 (m,1H), 4.36-4.32 (br.-d, 2H), 4.01, 3.99, and 3.58 (s for each, 3H),3.21-2.99 (m, 4H), 2.67 and 2.42 (s for each, 3H), 1.87-1.82 (br.-d,2H).

IR (KBr tab.) (cm⁻¹): 1698, 1658, 1509, 1432, 1242.

Melting Point (ether): 253°-254° C.

EXAMPLE 61

3-[1-(6,7-Dimethoxy-2-propyl-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-quinazoline(Compound 82)

The procedure similar to that described in Example 40 was repeated,except that 354.0 mg (1.0 mmol) of1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)-quinazolinehydrobromide (Compound v) obtained in Example 41 was used,4-chloro-6,7-dimethoxy-2-propylquinazoline was used in place of4-chloro-6,7-dimethoxyquinazoline, and isopropyl alcohol was used as areaction solvent in place of methanol. As a result, 174.3 mg (yield:35%) of Compound 82 was obtained as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.02 (d, 1H, J=1.0 Hz), 7.49 (dd, 1H, J=8.0, 1.0Hz), 7.22 (s, 1H), 7.17 (s, 1H), 7.08 (d, 1H, J=8.0 Hz), 5.31-5.23 (m,1H), 4.34-4.30 (br.-d, 2H), 4.01, 3.99, and 3.58 (s for each, 3H),3.20-3.02 (m, 4H), 2.86 (dist.-t, 2H), 2.42 (s, 3H), 1.93-1.81 (br.-d,2H), 1.24 (t, 3H, J=7.0 Hz).

IR (KBr tab.) (cm⁻¹): 1704, 1659, 1507, 1476, 1435, 1210.

Melting Point (ethyl acetate-ether): 206°-207° C.

EXAMPLE 62

1,2,3,4-Tetrahydro-3-[1-(2-isopropyl-6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,6-dimethyl-2,4-dioxoquinazoline (Compound 83)

The procedure similar to that described in Example 40 was repeated,except that 354.0 mg (1.0 mmol) of1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)quinazolinehydrobromide (Compound v) obtained in Example 41 was used and4-chloro-2-isopropyl-6,7-dimethoxyquinazoline was used in place of4-chloro-6,7-dimethoxyquinazoline. As a result, 50.3 mg (yield: 10%) ofCompound 83 was obtained as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.02 (d, 1H, J=1.5 Hz), 7.49 (dd, 1H, J=8.5, 1.5Hz), 7.23 (s, 1H), 7.17 (s, 1H), 7.09 (d, 1H, J=8.5 Hz), 5.33-5.23 (m,1H), 4.36-4.31 (br.-d, 2H), 4.01, 3.99, and 3.57 (s for each, 3H),3.21-2. 98 (m, 5H), 2.42 (s, 3H), 1.84-1.79 (br.-d, 2H), 1.37 (d, 6H,J=6.9 Hz).

IR (KBr tab.) (cm⁻¹): 1698, 1652, 1501, 1421, 1241, 1208.

Melting Point (hexane-ether): 172°-173° C.

EXAMPLE 63

1,2,3,4-Tetrahydro-3-[1-(6-methoxy-4-quinazolinyl)-4-piperidinyl]-1,6-dimethyl-2,4-dioxoquinazoline(Compound 84)

The procedure similar to that described in Example 57 was repeated,except that 1.06 g (3.0 mmol) of1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)-quinazolinehydrobromide (Compound v) obtained in Example 41 was used and4-chloro-6-methoxyquinazoline was used in place of4-chloro-6,7-dimethoxy-quinazoline. As a result, 154.4 mg (yield: 12%)of Compound 84 was obtained as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.69 (s, 1H), 8.01 (d, 1H, J=2.0 Hz), 7.98 (d,1H, J=9.0 Hz), 7.49 (dd, 1H, J=8.5, 2.0 Hz), 7.41 (dd, 1H, J=9.0, 2.5Hz), 7.24 (d, 1H, J=2.5 Hz), 7.08 (d, 1H, J=8.5 Hz), 5.40-5.25 (m, 1H),4.44-4.40 (br.-d, 2H), 3.93 and 3.57 (s for each, 3H), 3.48-3.04 (m,4H), 2.41 (s, 3H), 1.89-1.84 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1699, 1655, 1505, 1453, 1331, 1211, 1038.

Melting Point (methanol): 203°-205° C.

EXAMPLE 64

1,2,3,4-Tetrahydro-3-[1-(7-methoxy-4-quinazolinyl)-4-piperidinyl]-1,6-dimethyl-2,4-dioxoquinazoline(Compound 85)

The procedure similar to that described in Example 57 was repeated,except that 354.0 g (1.0 mmol) of1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)-quinazolinehydrobromide (Compound v) obtained in Example 41 was used and4-chloro-7-methoxyquinazoline was used in place of4-chloro-6,7-dimethoxyquinazoline. As a result, 96.2 mg (yield: 22%) ofCompound 85 was obtained as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.67 (s, 1H), 8.01 (d, 1H, J=1.5 Hz), 7.85 (d,1H, J=9.2 Hz), 7.49 (dd, 1H, J=8.0, 1.5 Hz), 7.28 (d, 1H, J=2.5 Hz),7.09 (d, 1H, J=8.0 Hz), 7.06 (dd, 1H, J=9.2, 2.5 Hz), 5.37-5.25 (m, 1H),4.50-4.45 (br.-d, 2H), 3.95 and 3.58 (s for each, 3H), 3.27-3.18 (br.-t,2H), 3.12-2.96 (m, 2H), 2.42 (s, 3H), 1.88-1.84 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1699, 1654, 1610, 1436, 1333, 1219.

Melting Point (ethyl acetate-ether): 232°-233° C.

1,2,3,4-Tetrahydro-I,6-dimethyl-2,4-dioxo-3-[1-(6,7,8-trimethoxy-4-quinazolinyl)-4-piperidinyl]quinazoline(Compound 86)

The procedure similar to that described in Example 57 was repeated,except that 1.06 g (3.0 mmol) of1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)-quinazolinehydrobromide (Compound v) obtained in Example 41 was used and4-chloro-6,7,8-trimethoxyquinazoline was used in place of4-chloro-6,7-dimethoxyquinazoline. As a result, 365.1 mg (yield: 25%) ofCompound 86 was obtained as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.73 (s, 1H), 8.00 (d, 1H, J=1.5 Hz), 7.48 (dd,1H, J=8.5, 1.5 Hz), 7.07 (d, 1H, J=8.5 Hz), 7.01 (s, 1H), 5.34-5.24 (m,1H), 4.35-4.31 (br.-d, 2H), 4.13, 4.05, 3.97, and 3.57 (s for each, 3H),3.21-3.02 (m, 4H), 2.41 (s, 3H), 1.86-1.81 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1700, 1654, 1480, 1339, 1128, 810.

Melting Point (ethyl acetate-ether): 172°-175° C.

EXAMPLE 66

3-[1-(7-Benzyloxy-6-methoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline(Compound 87)

The procedure similar to that described in Example 57 was repeated,except that 369.0 mg (1.05 mmol) of1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)-quinazolinehydrobromide (Compound v) obtained in Example 41 was used and7-benzyloxy-4-chloro-6-methoxyquinazoline was used in place of4-chloro-6,7-dimethoxyquinazoline. As a result, 233.8 mg (yield: 42%) ofCompound 87 was obtained as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.66 (s, 1H), 8.01 (d, 1H, J=1.5 Hz), 7.50-7.28(m, 7H), 7.21 (s, 1H), 7.08 (d, 1H, J=8.5 Hz), 5.30 (s, 2H), 5.29-5.24(m, 1H), 4.34-4.30 (br.-d, 2H), 4.01 and 3.58 (s for each, 3H),3.22-3.04 (m, 4H), 2.42 (s, 3H), 1.86-1.82 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1697, 1655, 1513, 1506, 1329, 754.

Melting Point (ether): 164°-168° C.

EXAMPLE 67

3-[1-(6,7-Dibenzyloxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline(Compound 88)

The procedure similar to that described in Example 61 was repeated,except that 836.0 mg (2.36 mmol) of1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)-quinazolinehydrobromide (Compound v) obtained in Example 41 was used and6,7-dibenzyloxy-4-chloroquinazoline was used in place of4-chloro-6,7-dimethoxyquinazoline. As a result, 786.3 mg (yield: 54%) ofCompound 88 was obtained as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.62 (s, 1H), 8.02 (d, 1H, J=1.5 Hz), 7.53-7.21(m, 12H), 7.16 (s, 1H), 7.09 (d, 1H, J=8.5 Hz), 5.33 (s, 4H), 5.21-5.19(m, 1H), 4.10-4.06 (br.-d, 2H), 3.59 (s, 3H), 3.06-2.95 (m, 4H), 2.43(s, 3H), 1,72-1.68 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1702, 1658, 1511, 1445, 1339, 1246, 1204.

Melting Point (ethyl acetate-ether): 172°-174° C.

EXAMPLE 68

3-[1-(6,7-Diethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline(Compound 98)

The procedure similar to that described in Example 57 was repeated,except that 354.0 mg (1.00 mmol) of1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)-quinazolinehydrobromide (Compound v) obtained in Example 41 was used and4-chloro-6,7-diethoxyquinazoline was used in place of4-chloro-6,7-dimethoxyquinazoline. As a result, 116.8 mg (yield: 24%) ofCompound 98 was obtained as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.65 (s, 1H), 8.02 (d, 1H, J=1.5 Hz), 7.49 (dd,1H, J=8.5, 1.5 Hz), 7.28 (s, 1H), 7.19 (s, 1H), 7.09 (d, 1H, J=8.5 Hz),5.33-5.25 (m, 1H), 4.38-4.33 (br.-d, 2H), 4.26 (q, 2H, J=7.0 Hz), 4.20(q, 2H, J=7.0 Hz), 3.58 (s, 3H), 3.24-2.99 (m, 4H), 2.42 (s, 3H),1.87-1.83 (br.-d, 2H), 1.55 (t, 3H, J=7.0 Hz), 1.54 (t, 3H, J=7.0 Hz).

IR (KBr tab.) (cm⁻¹): 1709, 1656, 1505, 1440, 1035.

Melting Point (ethyl acetate-ether): 173°-175° C.

EXAMPLE 69

1,2,3,4-Tetrahydro-1,6-dimethyl-3-[1-(6,7-methylene-dioxy-4-quinazolinyl)-4-piperidinyl]-2,4-dioxoquinazoline(Compound 99)

The procedure similar to that described in Example 40 was repeated,except that 262.0 mg (0.74 mmol) of1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)-quinazolinehydrobromide (Compound v) obtained in Example 41 was used and4-chloro-6,7-methylenedioxyquinazoline was used in place of4-chloro-6,7-dimethoxyquinazoline. As a result, 65.8 mg (yield: 20%) ofCompound 99 was obtained as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.63 (s, 1H), 8.02 (d, 1H, J=2.0 Hz), 7.50 (dd,1H, J=8.5, 2.0 Hz), 7.38 (s, 1H), 7.23 (s, 1H), 7.10 (d, 1H, J=8.5 Hz),6.14 (s, 2H), 5.35-5.26 (m, 1H), 4.39-4.34 (br.-d, 2H), 3.58 (s, 3H),3.24-3.16 (br.-t, 2H), 3.10-2.98 (m, 2H), 2.43 (s, 3H), 1.88-1.84(br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1695, 1648, 1490, 1448, 1035.

Melting Point (ethyl acetate-ether): 219°-220° C. (decomposition)

EXAMPLE 70

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-nitro-2,4-dioxo-1-(2-phthalimido-ethyl)quinazoline(Compound 33)

The procedure similar to that described in Example 1 was repeated,except that 478.0 mg (1.00 mol) of Compound 24 was used andN-(2-bromoethyl)phthalimide was used in place of methyl iodide. As aresult, 200 mg (yield: 31%) of Compound 33 was obtained as pale yellowcrystals.

¹ H-NMR (CDCl₃) δ(ppm): 9.04 (d, 1H, J=2.5 Hz), 8.65 (s, 1H), 8.41 (dd,1H, J=8.9, 2.5 Hz), 7.81-7.78 (m, 2H), 7.72-7.69 (m, 2H), 7.46 (s, 1H),7.44 (d, 1H, J=8.9 Hz), 7.14 (s, 1H), 5.26-5.17 (m, 1H), 4.48 (t, 2H,J=6.0 Hz), 4.42-4.38 (br.-d, 2H), 4.12 (t, 2H, J=6.0 Hz), 4.06 and 4.01(s for each, 3H), 3.26-3.16 (br.-t, 2H), 2.95-2.83 (m, 2H), 1.82-1.79(br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1710, 1669, 1616, 1504, 1457, 1428, 1395, 1333,1212, 719.

Melting Point (chloroform-methanol): 143° C.

EXAMPLE 71

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-nitro-2,4-dioxo-1-(3-phthalimido-propyl)quinazoline(Compound 34)

The procedure similar to that described in Example 1 was repeated,except that 478.0 mg (1.00 mol) of Compound 24 was used andN-(3-bromopropyl)phthalimide was used in place of methyl iodide. As aresult, 280 mg (yield: 42%) of Compound 34 was obtained as a pale yellowamorphous solid.

¹ H-NMR (CDCl₃) δ(ppm): 9.05 (d, 1H, J=2.5 Hz), 8.68 (s, 1H), 8.47 (dd,1H, J=8.9, 2.5 Hz), 7.86-7.81 (m, 2H), 7.76-7.71 (m, 2H), 7.34 (s, 1H),7.26 (d, 1H, J=8.9 Hz), 7.16 (s, 1H), 5.27-5.19 (m, 1H), 4.41-4.36(br.-d, 2H), 4.30-4.25 (dist.-t, 2H), 4.04 and 4.01 (s for each, 3H),3.87 (t, 2H, J=7.0 Hz), 3.25-3.16 (br.-t, 2H), 3.01-2.88 (m, 2H),2.25-2.14 (m, 2H), 1.89-1.85 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1702, 1657, 1615, 1498, 1430, 1330, 1214, 717.

EXAMPLE 72

1-(2-Aminoethyl)-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline(Compound 29)

In a solvent mixture of 5 ml of ethanol and 5 ml of chloroform wasdissolved 160.0 mg (0.25 mmol) of Compound 33 obtained in Example 70,and 0.04 ml (0.81 mmol) of hydrazine hydrate was added thereto, followedby heating at 60° C. for 1 hour. The solvent was distilled off underreduced pressure, and chloroform was added to the residue. Theprecipitated crystals were filtered off, and the filtrate was evaporatedunder reduced pressure. The residue was dissolved in a small amount ofchloroform, and a saturated solution of hydrogen chloride in ethylacetate was added thereto. The precipitated crystals were collected byfiltration and purified by washing with chloroform and diethyl ether togive 113.7 mg (yield: 78%) of the dihydrochloride of Compound 29 as paleyellow crystals.

¹ H-NMR (DMSO-d₆) δ(ppm): 8.83 (s, 1H), 8.76 (d, 1H, J=2.5 Hz), 8.53(dd, 1H, J=9.0, 2.5 Hz), 7.86 (d, 1H, J=9.0 Hz), 7.38 (s, 1H), 7.37 (s,1H), 5.32-5.25 (m, 1H), 4.86-4.81 (br.-d, 2H), 4.50-4.40 (br.-t, 2H),4.00 and 3.96 (s for each, 3H), 3.74-3.65 (br.-t, 2H), 3.10-3.00 (m,2H), 2.70-2.67 (m, 2H), 2.00-1.96 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 3400 (br), 1710, 1659, 1615, 1499, 1334.

Melting Point (chloroform-ether): 263° C.

EXAMPLE 73

1-(2-Aminopropyl)-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline(Compound 30)

The procedure similar to that described in Example 72 was repeated using128.1 mg (0.19 mmol) of Compound 34 obtained in Example 71, whereby 46.4mg (yield: 40%) of the dihydrochloride of Compound 30 was obtained aspale yellow crystals.

¹ H-NMR (DMSO-d₆) δ(ppm): 8.83 (s, 1H), 8.76 (d, 1H, J=2.5 Hz), 8.51(dd, 1H, J=9.0, 2.5 Hz), 7.83 (d, 1H, J=9.0 Hz), 7.40 (s, 1H), 7.38 (s,1H), 5.38-5.22 (m, 1H), 4.86-4.82 (br.-d, 2H), 4.30-4.20 (br.-t, 2H),4.00 and 3.97 (s for each, 3H), 3.75-3.66 (br.-t, 2H), 2.96-2.94 (m,2H), 2.75-2.67 (m, 2H), 1.98-1.95 (br.-d, 4H).

IR (KBr tab.) (cm⁻¹): 3400 (br), 1711, 1656, 1614, 1500, 1330.

Melting Point (chloroform-ether): 260° C.

EXAMPLE 74

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-methoxy-1-methyl-2,4-dioxoquinazoline(Compound 69)

The procedure similar to that described in Example 1 was repeated,except that 251.0 mg (0.56 mmol) of3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-hydroxy-2,4-dioxoquinazoline(Compound 102) obtained in Reference Example 13 was used in place ofCompound 24 and 3 equivalents of methyl iodide and 3 equivalents ofsodium hydride were used. As a result, 197.2 mg (yield: 74%) of Compound69 was obtained as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.68 (s, 1H), 7.66 (d, 1H, J=2.5 Hz), 7.31 (s,1H), 7.27 (dd, 1H, J=8.5, 2.5 Hz), 7.19 (s, 1H), 7.13 (d, 1H, J=8.5 Hz),5.34-5.26 (m, 1H), 4.41-4.36 (br.-d, 2H), 4.04, 4.01, 3.88, and 3.59 (sfor each, 3H), 3.26-3.00 (m, 4H), 1.88-1.85 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1696, 1653, 1502.

Melting Point (ethyl acetate-ether): 211°-212° C. (decomposition)

EXAMPLE 75

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-6-ethoxy-1-ethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline(Compound 72)

The procedure similar to that described in Example 74 was repeated,except that 150.0 mg (0.33 mmol) of Compound 102 was used and ethyliodide was used in place of methyl iodide. As a result, 121.2 mg (yield:73%) of Compound 72 was obtained as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.67 (s, 1H), 7.65 (d, 1H, J=2.5 Hz), 7.31 (s,1H), 7.26 (dd, 1H, J=9.0, 2.5 Hz), 7.19 (s, 1H), 7.14 (d, 1H, J=9.0 Hz),5.33-5.24 (m, 1H), 4.40-4.36 (br.-d, 2H), 4.17 (q, 2H, J=7.0 Hz), 4.10(q, 2H, J=7.0 Hz), 4.04 and 4.01 (s for each, 3H), 3.26-3.00 (m, 4H),1.90-1.89 (br.-d, 2H), 1.44 (t, 3H, J=7.0 Hz), 1.35 (t, 3H, J=7.0 Hz).

IR (KBr tab.) (cm⁻¹): 1696, 1657, 1506, 1341.

Melting Point (ethyl acetate-ether): 207°-209° C.

EXAMPLE 76

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-2,4-dioxo-6-propoxy-1-propyl-quinazoline(Compound 73)

The procedure similar to that described in Example 74 was repeated,except that 150.0 mg (0.33 mmol) of Compound 102 was used and propyliodide was used in place of methyl iodide. As a result, 110.2 mg (yield:63%) of Compound 73 was obtained as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.67 (s, 1H), 7.65 (d, 1H, J=3.0 Hz), 7.33 (s,1H), 7.26 (dd, 1H, J=9.0, 3.0 Hz), 7.19 (s, 1H), 7.09 (d, 1H, J=9.0 Hz),5.30-5.25 (m, 1H), 4.41-4.36 (br.-d, 2H), 4.07-3.96 (m, 4H), 4.04 and4.01 (s for each, 3H), 3.26-3.03 (m, 4H), 1.88-1.72 (m, 6H), 1.05 (t,3H, J=7.0 Hz), 1.03 (t, 3H, J=7.0 Hz).

IR (KBr tab.) (cm⁻¹): 1691, 1652, 1503, 1208.

Melting Point (ethyl acetate-ether): 179°-180° C.

EXAMPLE 77

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1-ethyl-1,2,3,4-tetrahydro-6-methoxy-2,4-dioxoquinazoline(Compound 70)

The procedure similar to that described in Example 1 was repeated,except that 100.0 mg (0.21 mmol) of Compound 66 obtained in Example 51was used in place of Compound 24. As a result, 65.6 mg (yield: 64%) ofCompound 70 was obtained as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.68 (s, 1H), 7.67 (d, 1H, J=2.9 Hz), 7.28-7.25(m, 2H), 7.19 (s, 1H), 7.15 (d, 1H, J=8.5 Hz), 5.34-5.24 (m, 1H),4.38-4.33 (br.-d, 2H), 4.17 (q, 2H, J=7.0 Hz), 4.03, 4.01, and 3.88 (sfor each, 3H), 3.25-3.02 (m, 4H), 1.89-1.84 (br.-d, 2H), 1.36 (t, 3H,J=7.0 Hz).

IR (KBr tab.) (cm⁻¹): 1699, 1654, 1505, 1426.

Melting Point (ethyl acetate-ether): 227°-229° C.

EXAMPLE 78

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-methoxy-2,4-dioxo-1-propyl-quinazoline(Compound 71)

The procedure similar to that described in Example 1 was repeated,except that 100.0 mg (0.20 mmol) of Compound 67 obtained in Example 52was used in place of Compound 24. As a result, 51.1 mg (yield: 50%) ofCompound 71 was obtained as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.68 (s, 1H), 7.66 (d , 1H, J=3.0 Hz), 7.29-7.26(m, 2H), 7.19 (s, 1H), 7.11 (d, 1H, J=9.0 Hz), 5.35-5.24 (m, 1H),4.39-4.35 (br.-d, 2H), 4.08 (dist.-t, 2H), 4.04, 4.01, and 3.88 (s foreach, 3H), 3.25-3.04 (m, 4H), 1.88-1.73 (m, 4H), 1.04 (t, 3H, J=7.0 Hz).

IR (KBr tab.) (cm⁻¹): 1699, 1654, 1502, 1476, 1428, 1327, 1213.

Melting Point (ethyl acetate-ether): 171°-172° C.

EXAMPLE 79

1,2,3,4-Tetrahydro-3-[1-(7-hydroxy-6-methoxy-4-quinazolinyl)-4-piperidinyl]-1,6-dimethyl-2,4-dioxoquinazoline(Compound 89)

In 10 ml of ethanol was dissolved 150 mg (0.28 mmol) of Compound 87obtained in Example 66, and 30 mg of 10% palladium on carbon was addedthereto, followed by vigorous stirring at room temperature for 6 hoursunder a hydrogen atmosphere at atmospheric pressure. The reactionmixture was filtered using a filter aid, and the filtrate wasconcentrated under reduced pressure. To the residue were added ethanoland ethyl acetate. The precipitated crystals were collected byfiltration, washed, and dried to give 105.2 mg (yield: 84%) of Compound89 as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.69 (s, 1H), 8.01 (d, 1H, J=1.5 Hz), 7.49 (dd,1H, J=8.5, 1.5 Hz), 7.34 (s, 1H), 7.19 (s, 1H), 7.08 (d, 1H, J=8.5 Hz),5.33-5.24 (m, 1H), 4.32-4.29 (br.-d, 2H), 4.03 and 3.58 (s for each,3H), 3.22-3.04 (m, 4H), 2.42 (s, 3H), 1.87-1.83 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1701, 1657, 1511, 1463, 1424, 799.

Melting Point (ethyl acetate-ether): 265°-266° C. (decomposition)

EXAMPLE 80

1,2,3,4-Tetrahydro-3-[1-(6-hydroxy-7-methoxy-4-quinazolinyl)-4-piperidinyl]-1,6-dimethyl-2,4-dioxoquinazoline(Compound 90)

In 5 ml of DMF was suspended 360 mg (9.0 mmol) of 60% sodium hydride,and a solution of 0.92 ml (9.0 mmol) of thiophenol in 10 ml of DMF wasadded dropwise to the suspension under ice cooling. After stirring for10 minutes, a solution of 1.38 g (3.0 mmol) of Compound 50 obtained inExample 41 in 10 ml of DMF was added thereto under ice cooling, followedby stirring at 100° C. for 10 hours. After the reaction mixture wascooled to room temperature, water was added thereto, and the mixture wasextracted with chloroform. The aqueous layer was adjusted to pH 5 byaddition of 4N hydrochloric acid and extracted with chloroform. Thecombined organic layer was washed with an aqueous solution of sodiumchloride and dried. The solvent was distilled off, and the residue waspurified by silica gel column chromatography (eluent:chloroform/methanol=50/1). The compound eluted as a component with lowpolarity was recrystallized from ether to give 302.8 mg (yield: 23%) ofCompound 90 as white crystals. The substance eluted as a component withhigh polarity was recrystallized from ether/ethanol to give 787.9 mg(yield: 59%) of Compound 89 as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.64 (s, 1H), 8.01 (d, 1H, J=1.5 Hz), 7.48 (dd,1H, J=9.0, 1.5 Hz), 7.36 (s, 1H), 7.25 (s, 1H), 7.08 (d, 1H, J=9.0 Hz),5.30-5.22 (m, 1H), 4.37-4.33 (br.-d, 2H), 4.04 and 3.57 (s for each,3H), 3.19-3.01 (m, 4H), 2.42 (s, 3H), 1.83-1.78 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1703, 1655, 1509, 1492, 1443, 1211.

Melting Point (ether): 265°-267° C. (decomposition)

EXAMPLE 81

3-[1-(6,7-Dihydroxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline(Compound 97)

The procedure similar to that described in Example 79 was repeated,except that 200.0 mg (0.33 mmol) of Compound 88 obtained in Example 67was used in place of Compound 87 and DMF was used as a reaction solventin place of ethanol. As a result, 98.5 mg (yield: 70%) of Compound 97was obtained as white crystals.

¹ H-NMR (DMSO-d₆) δ(ppm): 10.4-9.8 (br, 2H), 8.43 (s, 1H), 7.87 (d, 1H,J=1.5 Hz), 7.60 (dd, 1H, J=8.5, 1.5 Hz), 7.57 (d, 1H, J=8.5 Hz), 7.26(s, 1H), 7.06 (s, 1H), 5.20-5.05 (m, 1H), 4.23-4.18 (br.-d, 2H), 3.51(s, 3H), 3.10-2.80 (m, 4H), 2.39 (s, 3H), 1.76-1.73 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 3400 (br), 1698, 1658, 1480, 1350.

Melting Point (DMF-water): 240°-245° C.

EXAMPLE 82

1,2,3,4-Tetrahydro-3-[1-(6-methoxy-7-propoxy-4-quinazolinyl)-4-piperidinyl]-1,6-dimethyl-2,4-dioxoquinazoline(Compound 91)

The procedure similar to that described in Example 1 was repeated,except that 223.5 mg (0.50 mmol) of Compound 89 obtained in Example 79was used in place of Compound 24 and propyl iodide was used in place ofmethyl iodide. As a result, a free base of Compound 91 was obtained,which was then converted to the hydrochloride in the similar manner asin Example 41 to give 229.9 mg (yield: 87%) of the hydrochloride ofCompound 91 as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.54 (s, 1H), 7.99 (d, 1H, J=2.0 Hz), 7.91 (s,1H), 7.51 (dd, 1H, J=8.0, 2.0 Hz), 7.16 (s, 1H), 7.11 (d, 1H, J=8.0 Hz),5.48-5.44 (m, 1H), 4.91-4.87 (br.-d, 2H), 4.24 (t, 2H, J=7.0 Hz), 3.98and 3.57 (s for each, 3H), 3.57-3.46 (br.-t, 2H), 3.11-2.92 (m, 2H),2.42 (s, 3H), 1.99-1.88 (m, 4H), 1.09 (t, 3H, J=7.0 Hz).

IR (KBr tab.) (cm⁻¹): 1697, 1657, 1510.

Melting Point (ether): 202°-203° C.

EXAMPLE 83

1,2,3,4-Tetrahydro-3-[1-(7-methoxy-6-propoxy-4-quinazolinyl)-4-piperidinyl]-1,6-dimethyl-2,4-dioxoquinazoline(Compound 92)

The procedure similar to that described in Example 1 was repeated,except that 100.0 mg (0.22 mmol) of Compound 90 obtained in Example 80was used in place of Compound 24 and propyl iodide was used in place ofmethyl iodide. As a result, 69.0 mg (yield: 64%) of Compound 92 wasobtained as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.67 (s, 1H), 8.01 (d, 1H, J=1.5 Hz), 7.48 (dd,1H, J=8.5, 1.5 Hz), 7.24 (s, 1H), 7.19 (s, 1H), 7.08 (d, 1H, J=8.5 Hz),5.28-5.24 (m, 1H), 4.35-4.30 (br.-d, 2H), 4.10 (dist.-t, 2H), 4.01 and3.58 (s for each, 3H), 3.22-3.02 (m, 4H), 2.42 (s, 3H), 1.99-1.81 (m,4H), 1.10 (t, 3H, J=7.0 Hz).

IR (KBr tab.) (cm⁻¹): 1703, 1652, 1503, 1329, 1210.

Melting Point (ether): 187°-188° C.

EXAMPLE 84

3-[1-(7-Ethoxycarbonylmethoxy-6-methoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline(Compound 93)

The procedure similar to that described in Example 1 was repeated,except that 500.0 mg (1.12 mmol) of Compound 89 obtained in Example 79was used in place of Compound 24 and ethyl bromoacetate was used inplace of methyl iodide. As a result, 530.0 mg (yield: 89%) of Compound93 was obtained as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.67 (s, 1H), 8.02 (d, 1H,

J=1.5 Hz), 7.49 (dd, 1H, J=8.5, 1.5 Hz), 7.23 (s, 1H), 7.12 (s, 1H),7.09 (d, 1H, J=8.5 Hz), 5.33-5.24 (m, 1H), 4.83 (s, 2H), 4.35-4.25 (m,4H), 4.02 and 3.58 (s for each, 3H), 3.23-3.04 (m, 4H), 2.42 (s, 3H),1.87-1.83 (br.-d, 2H), 1.31 (t, 3H, J=7.0 Hz).

IR (KBr tab.) (cm⁻¹): 1700, 1658, 1514, 1506.

Melting Point (DMF-water): 122°-124° C.

EXAMPLE 85

3-[1-(6-Ethoxycarbonylmethoxy-7-methoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline(Compound 94)

The procedure similar to that described in Example 1 was repeated,except that 500.0 mg (1.12 mmol) of Compound 90 obtained in Example 80was used in place of Compound 24 and ethyl bromoacetate was used inplace of methyl iodide. As a result, 323.3 mg (yield: 54%) of Compound94 was obtained as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.67 (s, 1H), 8.01 (d, 1H, J=1.5 Hz), 7.49 (dd,1H, J=8.5, 1.5 Hz), 7.29 (s, 1H), 7.19 (s, 1H), 7.09 (d, 1H, J=8.5 Hz),5.27-5.23 (m, 1H), 4.78 (s, 2H), 4.32-4.24 (m, 4H), 4.03 and 3.58 (s foreach, 3H), 3.21-2.99 (m, 4H), 2.42 (s, 3H), 1.84-1.81 (br.-d, 2H), 1.29(t, 3H, J=7.0 Hz).

IR (KBr tab.) (cm⁻¹): 1700, 1649, 1511.

Melting Point (ether): 187°-188° C.

EXAMPLE 86

3-{1-[7-(2-Dimethylaminoethyl)oxy-6-methoxy-4-quinazolinyl]-4-piperidinyl}-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline(Compound 96)

The procedure similar to that described in Example 1 was repeated,except that 223.5 mg (0.50 mmol) of Compound 89 obtained in Example 79was used in place of Compound 24, dimethylaminoethyl chloridehydrochloride was used in place of methyl iodide, 2 equivalents ofsodium hydride was used, and the reaction was conducted at 60° C.,whereby 192.2 mg (yield: 74%) of a free base of Compound 96 was obtainedas an amorphous substance. The obtained free base (160.5 mg, 0.31 mmol)was dissolved in 5 ml of acetone, and 0.04 ml (0.62 mmol) ofmethanesulfonic acid was added thereto, followed by stirring at roomtemperature for 30 minutes. The solvent was distilled off under reducedpressure, and ether was added to the residue. The precipitated crystalswere collected by filtration to give 208.1 mg (yield: 95%) of thedimethanesulfonate of Compound 96 as white crystals.

¹ H-NMR (CDCl₃) δ(ppm) (for free base): 8.68 (s, 1H), 8.01 (d, 1H, J=1.5Hz), 7.49 (dd, 1H, J=8.5, 1.5 Hz), 7.25 (s, 1H), 7.18 (s, 1H), 7.09 (d,1H, J=8.5 Hz), 5.33-5.24 (m, 1H), 4.34-4.28 (m, 4H), 3.98 and 3.58 (sfor each, 3H), 3.18-3.03 (m, 4H), 2.94 (t, 2H, J=6.0 Hz), 2.43 (s, 3H),2.42 (s, 6H), 1.87-1.83 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹) (for dimethanesulfonate): 1705, 1654, 1549, 1511,769.

Melting Point (ether): 181°-183° C.

EXAMPLE 87

3-[1-(7-Carboxymethyloxy-6-methoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline(Compound 95)

In 10 ml of methanol was dissolved 250.0 mg (0.47 mmol) of Compound 93obtained in Example 84, and 5 ml of a 2N aqueous solution of sodiumhydroxide was added thereto, followed by heating under reflux for 6hours. After cooling, the reaction mixture was neutralized by additionof 4N hydrochloric acid, and extracted with chloroform. The organiclayer was washed and dried, and the solvent was distilled off underreduced pressure. To the residue was added ether, and the precipitatedcrystals were collected by filtration and dried to give 77.8 mg (yield:33%) of Compound 95 as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.51 (s, 1H), 7.99 (d, 1H, J=1.5 Hz), 7.65 (s,1H), 7.49 (dd, 1H, J=8.5, 1.5 Hz), 7.13 (s, 1H), 7.08 (d, 1H, J=8.5 Hz),5.40-5.25 (m, 1H), 4.97 (s, 2H), 4.65-4.60 (br.-d, 2H), 4.00 and 3.56 (sfor each, 3H), 3.35-3.26 (br.-t, 2H), 3.03-2.95 (m, 2H), 2.41 (s, 3H),1.89-1.85 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 3600 (br), 1698, 1651, 1510.

Melting Point (ether): 199°-203° C.

EXAMPLE 88

3-[1-(6,7-Dimethoxy-1-phthalazinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxoquinazoline(Compound 77)

In 10 ml of acetic acid was dissolved 300 mg (0.61 mmol) of Compound 76obtained in Example 58, and 40 mg of 10% palladium on carbon suspendedin a small amount of water was added to the solution, followed byvigorous stirring at 40° C. for 3 hours under a hydrogen atmosphere atatmospheric pressure. The reaction mixture was filtered using a filteraid, and the filtrate was neutralized by addition of a saturated aqueoussolution of sodium bicarbonate and extracted with ethyl acetate. Theorganic layer was washed successively with water and a saturated aqueoussolution of sodium chloride, and then dried. The solvent was distilledoff under reduced pressure, and the residue was purified by silica gelcolumn chromatography (eluent: chloroform/methanol=50/1). Ether wasadded to the product, and the precipitated crystals were collected byfiltration, washed, and dried to give 52.9 mg (yield: 19%) of Compound77 as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 9.08 (s, 1H), 8.03 (d, 1H, J=2.0 Hz), 7.50 (dd,1H, J=9.0, 2.0 Hz), 7.39 (s, 1H), 7.16 (s, 1H), 7.10 (d, 1H, J=9.0 Hz),5.31-5.24 (m, 1H), 4.09 and 4.07 (s for each, 3H), 4.00-3.96 (br.-d,2H), 3.60 (s, 3H), 3.27-3.07 (m, 4H), 2.43 (s, 3H), 1.90-1.86 (br.-d,2H).

IR (KBr tab.) (cm⁻¹): 1699, 1660, 1648, 1505, 1422, 1311, 1118.

Melting Point (ether): 173°-175° C.

EXAMPLE 89

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-(1-hydroxyethyl)-1-methyl-2,4-dioxoquinazoline(Compound 60)

In a solvent mixture of 3ml of methanol and 3 ml of chloroform wasdissolved 200.0 mg (0.41 mmol) of Compound 63 obtained in Example 50,and sodium borohydride was added thereto in excess, followed by heatingat 60° C. for 30 minutes. After cooling, water was added to the reactionmixture, and the mixture was extracted with chloroform. The organiclayer was washed and dried, and the solvent was distilled off underreduced pressure. To the residue was added ether, and the precipitatedcrystals were collected by filtration and dried to give 146.4 mg (yield:73%) of Compound 60 as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.67 (s, 1H), 8.19 (d, 1H, J=2.0 Hz), 7.76 (dd,1H, J=8.5, 2.0 Hz), 7.24 (s, 1H), 7.19 (d, 1H, J=8.5 Hz), 7.18 (s, 1H),5.32-5.24 (m, 1H), 5.01 (q, 1H, J=6.3 Hz), 4.34-4.30 (br.-d, 2H), 4.03,4.01, and 3.60 (s for each, 3H), 3.22-3.00 (m, 4H), 1.87-1.82 (br.-d,2H), 1.53 (d, 3H, J=6.3 Hz).

IR (KBr tab.) (cm⁻¹): 3400 (br), 1703, 1647, 1504, 1212.

Melting Point (ether): 215°-217° C.

EXAMPLE 90

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-(2-hydroxy-2-propyl)-1-methyl-2,4-dioxoquinazoline(Compound 61)

In 3 ml of THF was suspended 246.5 mg (1.0 mmol) of thoroughly driedcerium chloride, and 1 ml of a 1M solution of methylmagnesium bromide inTHF was added thereto under an argon gas atmosphere, followed bystirring at room temperature for 1 hour. To the reaction mixture wasdropwise added a solution of 245.0 mg (0.50 mmol) of Compound 63obtained in Example 50 in 5 ml of THF, and the mixture was stirred atroom temperature for 3 hours. A saturated aqueous solution of ammoniumchloride was added thereto in excess to stop the reaction, followed byextraction with chloroform. The organic layer was washed and dried, andthe solvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (eluent:chloroform/methanol=100/1) and recrystallized from ether to give 78.8 mg(yield: 31%) of Compound 61 as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.67 (s, 1H), 8.28 (d, 1H, J=2.5 Hz), 7.90 (dd,1H, J=9.0, 2.5 Hz), 7.24 (s, 1H), 7.19 (s, 1H), 7.17 (d, 1H, J=9.0 Hz),5.29-5.24 (m, 1H), 4.35-4.30 (br.-d, 2H), 4.03, 4.01, and 3.60 (s foreach, 3H), 3.23-3.00 (m, 4H), 1.87-1.82 (br.-d, 2H), 1.63 (s, 6H).

IR (KBr tab.) (cm⁻¹): 3500 (br), 1703, 1647, 1501, 1472, 1427, 1030,984.

Melting Point (ether): 234°-236° C.

EXAMPLE 91

6-Carboxy-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline(Compound 62)

In a solvent mixture of 30 ml of 1,4-dioxane and 5 ml of chloroform wassuspended 245.0 mg (0.50 mmol) of Compound 63 obtained in Example 50.The suspension was added to a solution of hypobromous acid (3 mmol)which was prepared by adding 0.15 ml of bromine to a solvent mixture of3 ml of a 2N aqueous solution of sodium hydroxide and 1 ml of1,4-dioxane under ice cooling. The mixture was stirred at roomtemperature for one day, and then neutralized by addition of 4Nhydrochloric acid, followed by extraction with chloroform. The organiclayer was washed and dried, and the solvent was distilled off underreduced pressure. To the residue was added ether, and the precipitatedcrystals were collected by filtration and dried to give 52.4 mg (yield:21%) of Compound 62 as white crystals.

¹ H-NMR (DMSO-d₆) δ(ppm): 8.73 (s, 1H), 8.57 (d, 1H, J=2.0 Hz), 8.23(dd, 1H, J=8.5, 2.0 Hz), 7.53 (d, 1H, J=8.5 Hz), 7.30 (s, 1H), 7.24 (s,1H), 5.35-5.20 (m, 1H), 4.68-4.63 (br.-d, 2H), 3.98, 3.95, and 3.54 (sfor each, 3H), 3.45-3.30 (m, 2H), 2.80-2.65 (m, 2H), 1.90-1.85 (br.-d,2H).

IR (KBr tab.) (cm⁻¹): 3400-2800 (br), 1706, 1657, 1608, 1510, 1501,1210.

Melting Point (ether): 230° C. (decomposition)

EXAMPLE 92

6-Amino-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1-ethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline(Compound 64)

The procedure similar to that described in Example 14 was repeated,except that 5.6 g (11.1 mmol) of Compound 2 obtained in Example 2 wasused in place of Compound 1. As a result, 3.4 g (yield: 64%) of Compound64 was obtained as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.68 (s, 1H), 7.49 (m, 1H), 7.28 (s, 1H), 7.21(s, 1H), 7.04 (m, 2H), 5.32-5.23 (m, 1H), 4.37-4.33 (br.-d, 2H), 4.13(q, 2H, J=7.0 Hz), 4.03 and 4.01 (s for each, 3H), 3.23-3.01 (m, 4H),1.88-1.83 (br.-d, 2H), 1.33 (t, 3H, J=7.0 Hz)

IR (KBr tab.) (cm⁻¹): 3410, 1695, 1645, 1506, 1333, 1244.

Melting Point (ether): 243°-245° C.

EXAMPLE 93

6-Acetylamino-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1-ethyl-1,2,3,4-tetrahydro-2,4-dioxoquinazoline(Compound 65)

The procedure similar to that described in Reference Example 2 wasrepeated, except that 300.0 mg (0.63 mmol) of Compound 64 obtained inExample 92 was used in place of Compound 19. As a result, 248.6 mg(yield: 76%) of Compound 65 was obtained as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.67 (s, 1H), 8.25 (dd, 1H, J=8.9, 2.5 Hz), 8.00(d, 1H, J=2.5 Hz), 7.67 (br.-s, 1H, NH), 7.34 (s, 1H), 7.18 (d, 1H,J=8.9 Hz), 7.18 (s, 1H), 5.32-5.23 (m, 1H), 4.43-4.38 (br.-d, 2H), 4.17(q, 2H, J=7.3 Hz), 4.04 and 4.01 (s for each, 3H), 3.26-3.17 (br.-t,2H), 3.11-2.98 (m, 2H), 2.23 (s, 3H), 1.89-1.84 (br.-d, 2H), 1.35 (t,3H, J=7.3 Hz).

IR (KBr tab.) (cm⁻¹): 1690, 1660, 1649, 1502.

Melting Point (ethyl acetate): 203°-206° C.

EXAMPLE 94

Diastereomixture of3-[1-(6,7-dimethoxy-4-quinazolinyl)-3-methyl-4-piperidinyl]-1-ethyl-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline(Compound 103)

The procedure similar to that described in Example 15 was repeated,except that 210 mg (0.52 mmol) of3-(1-ethoxycarbonyl-3-methyl-4-piperidinyl)-1-ethyl-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline(Compound kk; diastereomixture) was used in place of Compound a, whereby203 mg of crude1-ethyl-1,2,3,4-tetrahydro-3-(3-methyl-4-piperidinyl)-6-nitro-2,4-dioxoquinazolinehydrobromide was obtained. The product was treated in the similar manneras in Example 15 to give 193 mg (yield: 72%) of Compound 103 as a 6:4diastereomixture.

¹ H-NMR (CDCl₃) δ(ppm): 9.09 (d, 1H, J=2.6 Hz), 8.69 (s, 1H), 8.51 (dd,1H, J=9.2, 2.6 Hz), 7.35 (s, 0.6H), 7.32 (d, 1H, J=9.2 Hz), 7.29 (s,1H), 7.17 (s, 0.4H), 5.25-5.15 (m, 0.6H), 5.1-4.8 (m, 0.4H), 4.45-4.1(m, 4H), 4.04 (s, 3H), 4.02 (s, 1.8H), 4.01 (s, 1.2H), 3.7-3.4 (m,1.2H), 3.3-3.15 (m, 1.4H), 3.0-2.8 (m, 0.8H), 2.55-2.45 (m, 0.6H),2.0-1.8 (m, 1H), 1.41 (t, 3H, J=7.3 Hz), 1.27 (d, 1.8H, J=7.3 Hz), 0.90(d, 1.2H, J=7.0 Hz).

IR (KBr tab.) (cm⁻¹): 1716, 1666, 1613, 1573, 1525, 1452, 1331.

EXAMPLE 95

Diastereomixture of3-[1-(6,7-dimethoxy-4-quinazolinyl)-3-ethyl-4-piperidinyl]-1,2,3,4-tetrahydro-1-methyl-6-nitro-2,4-dioxoquinazoline(Compound 104)

The procedure similar to that described in Example 15 was repeated,except that 61.1 mg (0.15 mmol) of3-(1-ethoxycarbonyl-3-ethyl-4-piperidinyl)-1,2,3,4-tetrahydro-1-methyl-6-nitro-2,4-dioxoquinazoline(Compound ll; diastereo-mixture) was used in place of Compound a,whereby 70.4 mg of crude3-(3-ethyl-4-piperidinyl)-1,2,3,4-tetrahydro-1-methyl-6-nitro-2,4-dioxoquinazolinehydrobromide was obtained. The product was treated in the similar manneras in Example 15 to give 30.4 mg (yield: 39%) of Compound 104 as a 6:4diastereomixture.

¹ H-NMR (CDCl₃) δ(ppm): 9.09 (d, 1H, J=2.4 Hz), 8.70 (s, 0.4H), 8.65 (s,0.6H), 8.53 (dd, 1H, J=8.9, 2.4 Hz), 7.41 (s, 0.6H), 7.33 (d, 1H, J=8.9Hz), 7.32 (s, 0.4H), 7.25 (s, 0.6H), 7.17 (s, 0.4H), 5.35-5.25 (m, 1H),4.45-4.25 (m, 2H), 4.05 (s, 3H), 4.03 (s, 3H), 3.68 (s, 3H), 3.8-3.5 (m,2H), 3.5-3.25 (m, 1H), 2.25-2.15 (m, 1H), 2.0-1.8 (m, 1H), 1.7-1.5 (m,1H), 1.5-1.3 (m, 1H), 0.92 (t, 1.2H, J=7.4 Hz), 0.80 (t, 1.8H, J=7.4Hz).

IR (KBr tab.) (cm⁻¹): 1711, 1657, 1605, 1505, 1425, 1324.

EXAMPLE 96

Diastereomixture of3-[1-(6,7-dimethoxy-4-quinazolinyl)-3-ethyl-4-piperidinyl]-1-ethyl-1,2,3,4-tetrahydro-6,8-dinitro-2,4-dioxoquinazoline(Compound 105)

The procedure similar to that described in Example 15 was repeated,except that 132.2 mg (0.29 mmol) of3-(1-ethoxycarbonyl-3-ethyl-4-piperidinyl)-1-ethyl-1,2,3,4-tetrahydro-6,8-dinitro-2,4-dioxoquinazoline(Compound mm; diastereomixture) was used in place of Compound a, whereby164.9 mg of crude1-ethyl-3-(3-ethyl-4-piperidinyl)-1,2,3,4-tetrahydro-6,8-dinitro-2,4-dioxoquinazolinehydrobromide was obtained. The product was treated in the similar manneras in Example 15 to give 75.8 mg (yield: 38%) of Compound 105 as a 7:3diastereomixture.

¹ H-NMR (CDCl₃) δ(ppm): 9.24 (d, 1H, J=2.5 Hz), 8.72 (d, 1H, J=2.5 Hz),8.67 (s, 1H), 7.34 (s, 0.7H), 7.30 (s, 0.3H), 7.22 (s, 0.7H), 7.16 (s,0.3H), 5.25-5.15 (m, 0.7H), 5.0-4.85 (m, 0.3H), 4.5-4.3 (m, 2H),4.15-3.9 (m, 3H), 4.04 (s, 3H), 4.03 (s, 3H), 3.6-3.1 (m, 1.4H), 3.1-2.7(m, 0.6H), 2.3-2.15 (m, 1H), 2.0-1.85 (m, 1H), 1.8-1.6 (m, 1H), 1.5-1.3(m, 1H), 1.33 (t, 2.1H, J=6.9 Hz), 1.21 (t, 0.9H, J=6.9 Hz), 0.93 (t,0.9H, J=7.4 Hz), 0.80 (t, 2.1H, J=7.2 Hz).

IR (KBr tab.) (cm⁻¹): 1724, 1674, 1614, 1542, 1498, 1448, 1333.

EXAMPLE 97

Tablets:

Tablets having the following composition were prepared in a conventionalmanner.

Compound 50 (100 g) obtained in Example 41, 226.8 g of lactose, and 60 gof potato starch were mixed, and 120 g of a 10% aqueous solution ofhydroxypropyl cellulose was added thereto. The resulting mixture waskneaded, granulated, dried, and subjected to size reduction in a usualmanner to prepare granules for tableting. The granules were mixed with1.2 g of magnesium stearate, and the mixture was tableted by means of atableting machine (Model RT-15 manufactured by Kikusui K.K.) havingpestles of 8 mm diameter to give tablets each containing 50 mg of theactive ingredient.

    ______________________________________                                        Prescription:                                                                 ______________________________________                                        Compound 50            50     mg                                              Lactose                113.4  mg                                              Potato starch          30     mg                                              Hydroxypropyl cellulose                                                                              6      mg                                              Magnesium stearate     0.6    mg                                                                     200    mg                                              ______________________________________                                    

EXAMPLE 98

Tablets:

Tablets having the following composition were prepared in a conventionalmanner.

Compound 24 (100 g) obtained in Reference Example 6, 226.8 g of lactose,and 60 g of potato starch were mixed, and 120 g of a 10% aqueoussolution of hydroxypropyl cellulose was added thereto. The resultingmixture was kneaded, granulated, dried, and subjected to size reductionin a usual manner to prepare granules for tableting. The granules weremixed with 1.2 g of magnesium stearate, and the mixture was tableted bymeans of a tableting machine (Model RT-15 manufactured by Kikusui K.K.)having pestles of 8 mm diameter to give tablets each containing 50 mg ofthe active ingredient.

    ______________________________________                                        Prescription:                                                                 ______________________________________                                        Compound 24            50     mg                                              Lactose                113.4  mg                                              Potato starch          30     mg                                              Hydroxypropyl cellulose                                                                              6      mg                                              Magnesium stearate     0.6    mg                                                                     200    mg                                              ______________________________________                                    

REFERENCE EXAMPLE 1

6-Amino-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-2,4-dioxoquinazoline(Compound 19)

The procedure similar to that described in Example 14 was repeated,except that 450.0 mg (0.94 mmol) of Compound 24 was used in place ofCompound 1. As a result, 150.0 mg (yield: 35.6%) of Compound 19 wasobtained as white crystals.

¹ H-NMR (DMSO-d₆) δ(ppm): 10.99 (s, 1H, NH), 8.56 (s, 1H), 7.23 (s, 1H),7.15 (s, 1H), 7.13 (d, 1H, J=7.4 Hz), 6.93-6.89 (m, 2H), 5.40-5.05(br.-s, 2H, NH₂), 5.20-5.05 (m, 1H), 4.36-4.32 (br.-d, 2H), 3.95 (s,3H), 3.93 (s, 3H), 3.22-3.12 (br.-t, 2H), 2.95-2.82 (m, 2H), 1.75-1.71(br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 3430, 3356, 1711, 1655, 1509, 1351, 1216.

Melting Point (ether): 278°-280° C.

REFERENCE EXAMPLE 2

6-Acetylamino-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-2,4-dioxoquinazoline(Compound 20)

In 10 ml of dichloromethane was dissolved 100 mg (0.22 mmol) of Compound19 obtained in Reference Example 1, and 0.06 ml (0.45 mmol) oftriethylamine and 0.02 ml (0.24 mmol) of acetic anhydride were addedthereto, followed by stirring at room temperature for 2 hours. Water wasadded to the reaction mixture, and the mixture was extracted withchloroform. The organic layer was washed and dried. The solvent wasdistilled off, and ether was added to the residual oily substance. Theprecipitated crystals were collected by filtration to give 69.1 mg(yield: 64%) of Compound 20 as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 9.90 (br.-s, 1H, NH), 8.66 (s, 1H), 8.03 (s,1H), 7.97 (d, 1H, J=8.4 Hz), 7.25 (s, 1H), 7.15 (s, 1H), 6.97 (d, 1H,J=8.4 Hz), 5.35-5.25 (m, 1H), 4.40-4.35 (br.-d, 2H), 4.01 (s, 3H), 3.97(s, 3H), 3.27-3.18 (br.-t, 2H), 3.09-3.01 (m, 2H), 2.20 (s, 3H),1.84-1.80 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 3400, 1711, 1663, 1504, 1430.

Melting Point (ether): 249°-250° C.

REFERENCE EXAMPLE 3

7-Chloro-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-2,4-dioxoquinazoline

(Compound 21)

The procedure similar to that described in Example 15 was repeated,except that 110.0 mg (0.31 mmol) of7-chloro-3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-2,4-dioxoquinazoline(Compound e) was used in place of Compound a, whereby 86.3 mg of crude7-chloro-1,2,3,4-tetrahydro-2,4-dioxo-3-(4-piperidinyl)quinazolinehydrobromide was obtained. The product (76.2 mg) was treated in thesimilar manner as in Example 15 to give 61.3 mg (yield: 48.2%) ofCompound 21 as white crystals.

¹ H-NMR (DMSO-d₆) δ(ppm): 11.42 (s, 1H, NH), 8.55 (s, 1H), 7.92 (d, 1H,J=8.4 Hz), 7.25-7.21 (m, 2H), 7.18 (s, 1H), 7.15 (s, 1H), 5.12-5.06 (m,1H), 4.35-4.30 (br.-d, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.21-3.12(br.-t, 2H), 2.83-2.78 (m, 2H), 1.78-1.74 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1718, 1668, 1607, 1477, 1347.

Melting Point (ethyl acetate-ether): 277°-279° C.

REFERENCE EXAMPLE 4

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-methyl-2,4-dioxoquinazoline(Compound 22)

The procedure similar to that described in Example 15 was repeated,except that 1.0 g (3.02 mmol) of3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-6-methyl-2,4-dioxoquinazoline(Compound f) was used in place of Compound a, whereby 876.3 mg of crude6-methyl-3-(4-piperidinyl)-1,2,3,4-tetrahydro-2,4-dioxoquinazolinehydrobromide was obtained. The product (300.0 mg) was treated in thesimilar manner as in Example 15 to give 356.3 mg (yield: 77.6%) ofCompound 22 as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.93 (s, 1H, NH), 8.69 (s, 1H), 7.92 (s, 1H),7.42 (d, 1H, J=8.5 Hz), 7.34 (s, 1H), 7.19 (s, 1H), 6.92 (d, 1H, J=8.5Hz), 5.35-5.20 (m, 1H), 4.43-4.38 (br.-d, 2H), 4.04 (s, 3H), 4.00 (s,3H), 3.29-3.19 (br.-t, 2H), 3.13-3.04 (m, 2H), 2.41 (s, 3H), 1.89-1.84(br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 3400, 1712, 1621, 1503, 1430.

Melting Point (DMF-water): >280° C.

REFERENCE EXAMPLE 5

8-Chloro-3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline(Compound 23)

The procedure similar to that described in Example 15 was repeated,except that 700.0 mg (1.77 mmol) of8-chloro-3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline(Compound g) was used in place of Compound a, whereby 462.2 mg of crude8-chloro-1,2,3,4-tetrahydro-6-nitro-2,4-dioxo-3-(4-piperidinyl)quinazolinehydrobromide was obtained. The product (300.0 mg) was treated in thesimilar manner as in Example 15 to give 330.8 mg (yield: 56.5%) ofCompound 23 as pale yellow crystals.

¹ H-NMR (CDCl₃ -DMSO-d₆) (ppm): 8.87 (d, 1H, J=2.5 Hz), 8.64 (s, 1H),8.50 (d, 1H, J=2.5 Hz), 7.29 (s, 1H), 7.18 (s, 1H), 5.26-5.17 (m, 1H),4.44-4.39 (br.-d, 2H), 4.04 (s, 3H), 4.01 (s, 3H), 3.28-3.19 (br.-t,2H), 3.12-3.02 (m, 2H), 1.90-1.86 (br.-d; 2H).

IR (KBr tab.) (cm⁻¹): 1723, 1663, 1619, 1509, 1342.

Melting Point (ether): >280° C.

REFERENCE EXAMPLE 6

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline(Compound 24)

In 150 ml of DMF was dissolved 3.0 g (8.09 mmol) of1,2,3,4-tetrahydro-6-nitro-2,4-dioxo-3-(4-piperidinyl)-quinazolinehydrobromide, and 1.7 g (8.09 mmol) of 4-chloro-6,7-dimethoxyquinazolineand 1.1 g (24 mmol) of potassium carbonate were added to the solution,followed by heating at 80° C. for 2 hours. Water was added to thereaction mixture, and the mixture was extracted with chloroform. Theorganic layer was washed with an aqueous solution of sodium chloride anddried. After the solvent was distilled off, ethanol and ether were addedto the residue. The precipitated crystals were collected by filtrationand washed with ether to give 3.28 g (yield: 85%) of Compound 24 aswhite crystals.

¹ H-NMR (DMSO-d₆) δ(ppm): 12.01 (s, 1H, NH), 8.67 (d, 1H, J=2.5 Hz),8.55 (s, 1H), 8.45 (dd, 1H, J=9.0, 2.5 Hz), 7.34 (d, 1H, J=9.0 Hz), 7.23(s, 1H), 7.15 (s, 1H), 5.09-5.04 (m, 1H), 4.37-4.32 (br.-d, 2H), 3.95(s, 3H), 3.93 (s, 3H), 3.27-3.23 (br.-t, 2H), 2.87-2.78 (m, 2H),1.81-1.77 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1721, 1661, 1506, 1484, 1446, 1338.

Melting Point (ether): 290°-292° C.

REFERENCE EXAMPLE 7

8-Chloro-3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-1-methyl-2,4-dioxoquinazoline(Compound a)

The procedure similar to that described in Example 1 was repeated,except that 2.0 g (5.69 mmol) of8-chloro-3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-2,4-dioxoquinazolinewas used in place of Compound 24, whereby 890.0 mg (yield: 43%) ofCompound a was obtained as a white amorphous substance.

¹ H-NMR (CDCl₃) δ(ppm): 8.11 (dd, 1H, J=7.5, 1.5 Hz), 7.65 (dd, 1H,J=7.5, 1.7 Hz), 7.18 (dd, 1H, J=7.5, 7.5 Hz), 4.99-4.93 (m, 1H),4.43-4.21 (br.-s, 2H), 4.14 (q, 2H, J=7.5 Hz), 3.80 (s, 3H), 2.95-2.85(br.-t, 2H), 2.73-2.60 (m, 2H), 1.67-1.62 (br.-d, 2H), 1.27 (t, 3H,J=7.5 Hz).

REFERENCE EXAMPLE 8

3-(1-Ethoxycarbonyl-4-piperidinyl)-1-ethyl-1,2,3,4-tetrahydro-6-methyl-2,4-dioxoquinazoline(Compound b)

The procedure similar to that described in Example 1 was repeated,except that 1.0 g (3.02 mmol) of3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-6-methyl-2,4-dioxoquinazoline(Compound f) was used in place of Compound 24 and ethyl iodide was usedin place of methyl iodide, whereby 855.0 mg (yield: 79%) of Compound bwas obtained as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 7.99 (d, 1H, J=1.5 Hz), 7.46 (dd, 1H, J=8.0, 1.5Hz), 7.07 (d, 1H, J=8.0 Hz), 5.16-5.05 (m, 1H), 4.41-4.25 (br.-s, 2H),4.18-4.10 (m, 4H), 2.96-2.63 (m, 4H), 2.40 (s, 3H), 1.66-1.62 (br.-d,2H), 1.32 (t, 3H, J=7.9 Hz), 1.27 (t, 3H, J=7.2 Hz).

REFERENCE EXAMPLE 9

3-(1-Ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-6-methyl-2,4-dioxo-1-propylquinazoline(Compound c)

The procedure similar to that described in Example 1 was repeated,except that 1.0 g (3.02 mmol) of3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-6-methyl-2,4-dioxoquinazoline(Compound f) was used in place of Compound 24 and propyl iodide was usedin place of methyl iodide, whereby 1.09 g (yield: 97%) of Compound c wasobtained as a colorless oily substance.

¹ H-NMR (CDCl₃) δ(ppm): 7.99 (d, 1H, J=1.5 Hz), 7.45 (dd, 1H, J=8.0, 1.5Hz), 7.04 (d, 1H, J=8.0 Hz), 5.16-5.07 (m, 1H), 4.46-4.25 (br.-s, 2H),4.14 (q, 2H, J=7.0 Hz), 4.05-3.99 (dist.-t, 2H), 2.96-2.63 (m, 4H), 2.40(s, 3H), 1.81-1.61 (m, 4H), 1.27 (t, 3H, J=7.0 Hz), 1.02 (t, 3H, J=7.3Hz).

REFERENCE EXAMPLE 10

8-Chloro-3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-1-methyl-6-nitro-2,4-dioxoquinazoline(Compound d)

The procedure similar to that described in Example 1 was repeated,except that 1.1 g (2.77 mmol) of8-chloro-3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline(Compound g) was used in place of Compound 24, whereby 259.8 mg (yield:23%) of Compound d was obtained as white crystals.

¹ H-NMR (CDCl₃) δ(ppm): 8.95 (d, 1H, J=3.0 Hz), 8.51 (d, 1H, J=3.0 Hz),4.99-4.94 (m, 1H), 4.35-4.31 (m, 2H), 4.15 (q, 2H, J=7.0 Hz), 3.86 (s,3H), 2.90-2.80 (br.-t, 2H), 2.69-2.55 (m, 2H), 1.68-1.63 (br.-d, 2H),1.28 (t, 3H, J=7.0 Hz).

REFERENCE EXAMPLE 11

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-5-methyl-2,4-dioxoquinazoline(Compound 100)

The procedure similar to that described in Example 15 was repeated,except that 1.00 g (3.17 mmol) of3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-5-methyl-2,4-dioxoquinazoline(Compound nn) was used in place of Compound a, whereby 854.1 mg of crude1,2,3,4-tetrahydro-5-methyl-2,4-dioxo-3-(4-piperidinyl) quinazolinehydrobromide was obtained. The product (850.0 mg) was treated in thesimilar manner as in Example 40 to give 1.02 g (yield: 72%) of Compound100 as white crystals.

¹ H-NMR (DMSO-d₆) δ(ppm): 11.2 (br, 1H, NH), 8.56 (s, 1H), 7.46 (dd, 1H,J=8.2, 7.5 Hz), 7.23 (s, 1H), 7.15 (s, 1H), 7.01 (d, 1H, J=8.2 Hz), 6.97(d, 1H, J=7.5 Hz), 5.15-5.05 (m, 1H), 4.36-4.31 (br.-d, 2H), 3.94 and3.92 (s for each, 3H), 3.18-3.12 (br.-t, 2H), 2.82-2.78 (m, 2H),1.75-1.71 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1708, 1661, 1505, 1477, 1352.

Melting Point (methanol-water): 283°-284° C. (decomposition)

REFERENCE EXAMPLE 12

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-8-methyl-2,4-dioxoquinazoline(Compound 101)

The procedure similar to that described in Example 15 was repeated,except that 1.00 g (3.17 mmol) of3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-8-methyl-2,4-dioxoquinazoline(Compound oo) was used in place of Compound a, whereby 960.0 mg of crude1,2,3,4-tetrahydro-8-methyl-2,4-dioxo-3-(4-piperidinyl)quinazolinehydrobromide was obtained. The product (900.0 mg) was treated in thesimilar manner as in Example 40 to give 1.09 g (yield: 82%) of Compound101 as white crystals.

¹ H-NMR (DMSO-d₆) δ(ppm): 11.4 (br, 1H, NH), 8.56 (s, 1H), 7.80 (d, 1H,J=8.0 Hz), 7.48 (d, 1H, J=7.0 Hz), 7.23 (s, 1H), 7.14 (s, 1H), 7.10 (dd,1H, J=8.0, 7.0 Hz), 5.20-5.00 (m, 1H), 4.35-4.31 (br.-d, 2H), 3.96 and3.92 (s for each, 3H), 3.22-3.13 (br.-t, 2H), 2.87-2.83 (m, 2H),1.78-1.75 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1706, 1651, 1506, 1418.

Melting Point (methanol-water): 267°-268° C. (decomposition)

REFERENCE EXAMPLE 13

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3,4-tetrahydro-6-hydroxy-2,4-dioxoquinazoline(Compound 102)

The procedure similar to that described in Example 15 was repeated,except that 500.0 mg (1.44 mmol) of3-(1-ethoxycarbonyl-4-piperidinyl)-1,2,3,4-tetrahydro-6-methoxy-2,4-dioxoquinazoline(Compound pp) was used in place of Compound a, whereby 338.6 mg of crude1,2,3,4-tetrahydro-6-hydroxy-2,4-dioxo-3-(4-piperidinyl)quinazolinehydrobromide was obtained. The product (330.0 mg) was treated in thesimilar manner as in Example 40 to give 362.0 mg (yield: 57%) ofCompound 102 as white crystals.

¹ H-NMR (DMSO-d₆) δ(ppm): 11.1 (br, 1H, NH), 9.58 (s, 1H, OH), 8.54 (s,1H), 7.28 (d, 1H, J=2.5 Hz), 7.22 (s, 1H), 7.15 (s, 1H), 7.10 (dd, 1H,J=9.0, 2.5 Hz), 7.02 (d, 1H, J=9.0 Hz), 5.14-5.05 (m, 1H), 4.35-4.31(br.-d, 2H), 3.95 and 3.93 (s for each, 3H), 3.21-3.11 (br.-t, 2H),2.91-2.79 (m, 2H), 1.75-1.71 (br.-d, 2H).

IR (KBr tab.) (cm⁻¹): 1703, 1662, 1506, 1482, 1433.

Melting Point (ether): 297°-298° C. (decomposition)

REFERENCE EXAMPLE 14

Diastereomixture of3-[1-(6,7-dimethoxy-4-quinazolinyl)-3-methyl-4-piperidinyl]-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline(Compound 106)

The procedure similar to that described in Example 15 was repeated,except that 500 mg (1.33 mmol) of3-(1-ethoxycarbonyl-3-methyl-4-piperidinyl)-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline(Compound qq; diastereomixture) was used in place of Compound a, whereby514.3 mg of crude1,2,3,4-tetrahydro-3-(3-methyl-4-piperidinyl)-6-nitro-2,4-dioxoquinazolinehydrobromide was obtained. The product (254.3 mg) was treated in thesimilar manner as in Example 15 to give 100.5 mg (yield: 31%) ofCompound 106 as a 7:3 diastereomixture.

¹ H-NMR (CDCl₃) δ(ppm): 8.97 (d, 1H, J=2.6 Hz), 8.68 (s, 1H), 8.38 (dd,1H, J=9.1, 2.6 Hz), 7.31 (d, 1H, J=9.1 Hz), 7.28 (s, 1H), 7.17 (s, 1H),5.2-5.1 (m, 0.3H), 5.0-4.7 (m, 0.7H), 4.45-4.2 (m, 1H), 4.06 (s, 3H),4.02 (s, 0.9H), 4.01 (s, 2.1H), 3.65-3.4 (m, 1H), 3.3-3.1 (m, 2H),3.0-2.85 (m, 1H), 2.0-1.8 (m, 1H), 1.22 (d, 0.9H, J=6.9 Hz), 0.92 (d,2.1H, J=7.4 Hz).

IR (KBr tab.) (cm⁻¹): 1726, 1675, 1511, 1480, 1433, 1338.

REFERENCE EXAMPLE 15

Diastereomixture of3-[1-(6,7-dimethoxy-4-quinazolinyl)-3-ethyl-4-piperidinyl]-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline(Compound 107)

The procedure similar to that described in Example 15 was repeated,except that 300 mg (0.77 mmol) of3-(1-ethoxycarbonyl-3-ethyl-4-piperidinyl)-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline(Compound rr; diastereomixture) was used in place of Compound a, whereby315 mg of crude3-(3-ethyl-4-piperidinyl)-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazolinehydrobromide was obtained. The product was treated in the similar manneras in Example 15 to give 167 mg (yield: 43%) of Compound 107 as a 6:4diastereomixture.

¹ H-NMR (CDCl₃) δ(ppm): 9.03 (d, 1H, J=2.6 Hz), 8.72 (s, 0.4H), 8.70 (s,0.6H), 8.46 (dd, 1H, J=8.9, 2.4 Hz), 7.33 (s, 1H), 7.24 (s, 0.6H), 7.22(d, 1H, J=8.9 Hz), 7.18 (s, 0.4H), 5.35-5.2 (m, 1H), 4.5-4.3 (m, 2H),4.03 (s, 6H), 3.6-3.4 (m, 2H), 3.4-3.25 (m, 1H), 2.25-2.15 (m, 1H),2.05-1.9 (m, 1H), 1.8-1.55 (m, 1H), 1.55-1.35 (m, 1H), 0.92 (t, 1.2H,J=7.3 Hz), 0.78 (t, 1.8H, J=7.4 Hz).

IR (KBr tab.) (cm⁻¹): 1722, 1657, 1610, 1510, 1429, 1332.

REFERENCE EXAMPLE 16

3-[1-(6,7-Dimethoxy-4-quinazolinyl)-3-piperidinyl]-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline(Compound 108)

The procedure similar to that described in Example 15 was repeated,except that 184 mg (0.51 mmol) of3-(1-ethoxycarbonyl-3-piperidinyl)-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline(Compound ss) was used in place of Compound a, whereby 173 mg of crude1,2,3,4-tetrahydro-6-nitro-2,4-dioxo-3-(3-piperidinyl)quinazolinehydrobromide was obtained. The product was treated in the similar manneras in Example 15 to give 193 mg (yield: 80%) of Compound 108.

¹ H-NMR (DMSO-d₆) δ(ppm): 12.01 (s, 1H), 8.63 (s, 1H), 8.54 (s, 1H),8.44 (d, 1H, J=8.9 Hz), 7.32 (d, 1H, J=8.9 Hz), 7.20 (s, 1H), 7.15 (s,1H), 5.25-5.05 (m, 1H), 4.2-4.05 (m, 2H), 4.05-3.9 (m, 1H), 3.93 (s,6H), 3.1-2.9 (m, 1H), 2.75-2.55 (m, 1H), 2.0-1.8 (m, 3H).

IR (KBr tab.) (cm⁻¹): 1724, 1667, 1610, 1503, 1481, 1429, 1333.

Industrial Applicability

According to the present invention, there is provided a drug containinga 1,2,3,4-tetrahydro-2,4-dioxoquinazoline derivative or apharmaceutically acceptable salt thereof as an active ingredient, whichhas an adenosine uptake inhibitory activity and is useful for theprotection of myocardium and for the prevention or suppression ofinflammation such as leg and foot edema.

We claim:
 1. A method of preventing or treating inflammatory edema,which comprises administering an effective amount of a1,2,3,4-tetrahydro-2,4-dioxoquinazoline derivative represented byformula (I): ##STR27## wherein R¹ represents hydrogen, substituted orunsubstituted lower alkyl, alkenyl or substituted or unsubstitutedaralkyl; R², R³, R⁴ and R⁵ independently represent hydrogen, halogen,amino, mono- or di (lower alkyl)amino, lower alkanoylamino, nitro,cyano, substituted or unsubstituted lower alkyl, hydroxy, lower alkoxy,lower alkylthio, carboxy, lower alkoxycarbonyl, lower alkanoyl,aralkyloxy, or lower alkanoyloxy; R⁶, R⁷, R⁸ and R⁹ independentlyrepresent hydrogen, hydroxy, substituted or unsubstituted lower alkoxy,or aralkyloxy; R¹⁰ represents hydrogen or lower alkyl; and Z is N and Yis C--R¹¹ (wherein R¹¹ represents hydrogen, substituted or unsubstitutedlower alkyl or halogen), or a pharmaceutically acceptable salt thereof.2. A method of preventing or treating inflammatory edema according toclaim 1, wherein R¹ represents hydrogen, substituted or unsubstitutedlower alkyl, allyl or substituted or unsubstituted aralkyl; R², R³, R⁴and R⁵ independently represent hydrogen, halogen, amino, mono- ordi(lower alkyl)amino, lower alkanoylamino, nitro, cyano, substituted orunsubstituted lower alkyl, hydroxy, lower alkoxy, lower alkoxycarbonyl,aralkyloxy, or lower alkanoyloxy; R⁶ and R⁹ each represents hydrogen; R⁷and R⁸ independently represent hydroxy or lower alkoxy; R¹⁰ representshydrogen; Y represents CH; Z represents N; and the 3-position of the2,4-dioxoquinazoline ring and the 4-position of the piperidine ring aredirectly connected.
 3. A 1,2,3,4-tetrahydro-2,4-dioxoquinazolinederivative represented by formula (I-a): ##STR28## wherein R^(1a)represents substituted or unsubstituted lower alkyl, alkenyl, orsubstituted or unsubstituted aralkyl; and R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, Y, and Z have the same meanings as defined in claim 1or apharmaceutically acceptable salt thereof.
 4. A1,2,3,4-tetrahydro-2,4-dioxoquinazoline derivative according to claim 3wherein R^(1a) represents substituted or unsubstituted lower alkyl,allyl, or substituted or unsubstituted aralkyl; R², R³, R⁴, and R⁵independently represent hydrogen, halogen, amino, mono- or di(loweralkyl)amino, lower alkanoylamino, nitro, cyano, substituted orunsubstituted lower alkyl, hydroxy, lower alkoxy, lower alkoxycarbonyl,aralkyloxy, or lower alkanoyloxy; R⁶ and R⁹ each represents hydrogen; R⁷and R⁸ independently represent hydroxy, or lower alkoxy; R¹⁰ representshydrogen; Y represents CH; Z represents N; and the 3-position of the2,4-dioxoquinazoline ring and the 4-position of the piperidine ring aredirectly connected, or a pharmaceutically acceptable salt thereof.
 5. A1,2,3,4-tetrahydro-2,4-dioxoquinazoline derivative according to claim 4wherein R⁷ and R⁸ each represents methoxy, or a pharmaceuticallyacceptable salt thereof.
 6. A 1,2,3,4-tetrahydro-2,4-dioxoquinazolinederivative according to claim 5 wherein R^(1a) represents substituted orunsubstituted lower alkyl, or a pharmaceutically acceptable saltthereof.
 7. A 1,2,3,4-tetrahydro-2,4-dioxoquinazoline derivativeaccording to claim 6 wherein R², R³, R⁴, and R⁵ independently representhydrogen or substituted or unsubstituted lower alkyl, or apharmaceutically acceptable salt thereof.
 8. A1,2,3,4-tetrahydro-2,4-dioxoquinazoline derivative according to claim 7wherein R^(1a) and R³ each represents methyl, and R², R⁴, and R⁵ eachrepresents hydrogen, or a pharmaceutically acceptable salt thereof.